Amino acid compounds and methods of use

ABSTRACT

The invention relates to compounds of formula (I): formula (I) or a salt thereof wherein R 1 , R 5 , R 7 , R 8 , X, m, n, p and q are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are αvβ6 integrin inhibitors that are useful for treating tissue specific fibrosis such as idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase filing under 35 U.S.C. § 371 ofInternational Application No. PCT/US2017/067622 having an InternationalFiling Date of Dec. 20, 2017, which claims priority benefit of U.S.Provisional Patent Application No. 62/438,951 filed Dec. 23, 2016, andof U.S. Provisional Patent Application No. 62/538,564 filed Jul. 28,2017. The entire contents of those applications are hereby incorporatedby reference herein.

TECHNICAL FIELD OF THE INVENTION

This invention relates to amino acid compounds, pharmaceuticalcompositions comprising the amino acid compounds, and methods of use ofthe compounds and compositions in treating diseases, such as fibroticdiseases.

BACKGROUND OF THE INVENTION

Fibrosis, a pathologic feature of many diseases, is caused by adysfunction in the body's natural ability to repair damaged tissues. Ifleft untreated, fibrosis can result in scarring of vital organs causingirreparable damage and eventual organ failure.

Patients with nonalcoholic fatty liver disease (NAFLD) may progress fromsimple steatosis to nonalcoholic steatohepatitis (NASH) and thenfibrosis. While liver fibrosis is reversible in its initial stages,progressive liver fibrosis can lead to cirrhosis.

Fibrosis in the kidney, characterized by glomerulosclerosis andtubulointerstitial fibrosis, is the final common manifestation of a widevariety of chronic kidney diseases (CKD). Irrespective of the initialcauses, progressive CKD often results in widespread tissue scarring thatleads to destruction of kidney parenchyma and end-stage renal failure, adevastating condition that requires dialysis or kidney replacement.

Scleroderma encompasses a spectrum of complex and variable conditionsprimarily characterized by fibrosis, vascular alterations, andautoimmunity. The scleroderma spectrum of disorders share the commonfeature of fibrosis, resulting in hardening or thickening of the skin.For some patients, this hardening occurs only in limited areas, but forothers, it can spread to other major organs.

Following myocardial infarction, cardiac structural remodeling isassociated with an inflammatory reaction, resulting in scar formation atthe site of the infarction. This scar formation is a result of fibrotictissue deposition which may lead to reduced cardiac function anddisruption of electrical activity within the heart.

Crohn's Disease is a chronic disease of unknown etiology tending toprogress even in the setting of medical or surgical treatment.Intestinal fibrosis is among the most common complications of Crohn'sdisease, resulting in stricture formation in the small intestine andcolon.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosingdisease of unknown etiology, occurring in adults and limited to thelungs. In IPF, the lung tissue becomes thickened, stiff, and scarred. Aslung fibrosis progresses, it becomes more difficult for the lungs totransfer oxygen into the bloodstream and the organs do not receive theoxygen needed to function properly. IPF currently affects approximately200,000 people in the U.S., resulting in 40,000 deaths per year.Patients diagnosed with IPF experience progressive breathlessness andeventually, complete respiratory failure.

Nonspecific interstitial pneumonia (NSIP) is a rare disorder thataffects the tissue that surrounds and separates the tiny air sacs of thelungs. These air sacs, called the alveoli, are where the exchange ofoxygen and carbon dioxide takes place between the lungs and thebloodstream. Interstitial pneumonia is a disease in which the mesh-likewalls of the alveoli become inflamed. The pleura (a thin covering thatprotects and cushions the lungs and the individual lobes of the lungs)might become inflamed as well. There are two primary forms ofNSIP—cellular and fibrotic. The cellular form is defined mainly byinflammation of the cells of the interstitium. The fibrotic form isdefined by thickening and scarring of lung tissue. This scarring isknown as fibrosis and is irreversible. When the lung tissue thickens orbecomes scarred, it does not function as effectively. Breathing becomesless efficient, and there are lower levels of oxygen in the blood.http://my.clevelandclinic.org/health/diseases_conditions/hic_Pneumonia/hic-nonspecific-interstitial-pneumonia.

Available courses of treatment are scarce, as there are currently nooptions on the market proven to have an effect on long-term patientsurvival or symptomatology. There remains a need for treatment offibrotic diseases.

The αvβ6 integrin is expressed in epithelial cells, and binds to thelatency-associated peptide of transforming growth factor-β1 (TGFβ1) andmediates TGFβ1 activation. Its expression level is significantlyincreased after injury to lung and cholangiocytes, and plays a criticalin vivo role in tissue fibrosis. Increased levels are also associatedwith increased mortality in IPF and NSIP patients.

Primary sclerosing cholangitis (PSC) involves bile duct inflammation,and fibrosis that obliterates the bile ducts. The resulting impedimentto the flow of bile to the intestines can lead to cirrhosis of the liverand subsequent complications such as liver failure and liver cancer.Expression of αvβ6 is elevated in liver and bile duct of PSC patients.

The present disclosure provides for αvβ6 integrin inhibitors that may beuseful for tissue-specific treatment of fibrosis.

BRIEF SUMMARY OF THE INVENTION

Disclosed are amino acid compounds that are αvβ6 integrin inhibitors,compositions containing these compounds and methods for treatingdiseases mediated by αvβ6 integrin such as a fibrotic disease.

In one aspect, provided is a compound of formula (I), or any variationthereof, or a salt thereof (e.g., a pharmaceutically acceptable saltthereof), as detailed herein. Also provided is a compound of (I-A), orany variation thereof, or a salt thereof (e.g., a pharmaceuticallyacceptable salt thereof), as detailed herein.

Further provided is a pharmaceutical composition comprising a compoundof formula (I), or any variation thereof detailed herein, or a saltthereof (e.g., a pharmaceutically acceptable salt thereof), and apharmaceutically acceptable carrier or excipient. Also provided is apharmaceutical composition comprising a compound of formula (I-A), orany variation thereof detailed herein, or a salt thereof (e.g., apharmaceutically acceptable salt thereof), and a pharmaceuticallyacceptable carrier or excipient.

In another aspect, provided is a method of treating a fibrotic diseasein an individual (such as a human) in need thereof comprisingadministering to the individual a therapeutically effective amount of acompound of formula (I), or any variation thereof detailed herein, or apharmaceutically acceptable salt thereof. In some embodiments, thefibrotic disease is pulmonary fibrosis, liver fibrosis, skin fibrosis,cardiac fibrosis, kidney fibrosis, gastrointestinal fibrosis, primarysclerosing cholangitis, or biliary fibrosis. A compound of formula(I-A), or any variation thereof, or a salt thereof (e.g., apharmaceutically acceptable salt thereof), as detailed herein may alsobe used in any of the methods detailed herein, such as in a method ofdelaying the onset and/or development of a fibrotic disease in anindividual (such as a human) who is at risk for developing a fibroticdisease.

In another aspect, provided is a method of delaying the onset and/ordevelopment of a fibrotic disease in an individual (such as a human) whois at risk for developing a fibrotic disease.

Also provided is a compound of formula (I), or any variation thereofdetailed herein, or a pharmaceutical composition thereof, for thetreatment of a fibrotic disease.

Also provided is use of a compound of formula (I), or any variationthereof detailed herein, or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for the treatment of a fibroticdisease. Also provided is use of a compound of formula (I-A), or anyvariation thereof detailed herein, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of afibrotic disease.

Further provided is a kit comprising a compound of formula (I), or anyvariation thereof detailed herein, or a pharmaceutically acceptable saltthereof. Further provided is a kit comprising a compound of formula(I-A), or any variation thereof detailed herein, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the kit comprisesinstructions for use according to a method described herein, such as amethod of treating a fibrotic disease in an individual.

In another aspect, provided is a method of making a compound of formula(I) or any variation thereof. Also provided is a method of making acompound of formula (I-A) or any variation thereof. Also provided arecompound intermediates useful in synthesis of a compound of formula (I)or (I-A), or any variation thereof.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides, inter alia, compounds of formula (I), andvariations thereof, pharmaceutical compositions comprising compounds offormula (I), and methods of using such compounds and compositions intreating fibrotic diseases. Also provided are compounds of formula(I-A), and variations thereof, pharmaceutical compositions comprisingcompounds of formula (I-A), and methods of using such compounds andcompositions in treating fibrotic diseases.

Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

“Alkyl” as used herein refers to and includes, unless otherwise stated,a saturated linear (i.e., unbranched) or branched univalent hydrocarbonchain or combination thereof, having the number of carbon atomsdesignated (i.e., C₁-C₁₀ means one to ten carbon atoms).

Particular alkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀alkyl”), having 1 to 10 carbon atoms (a “C₁-C₁₀ alkyl”), having 6 to 10carbon atoms (a “C₆-C₁₀ alkyl”), having 1 to 6 carbon atoms (a “C₁-C₆alkyl”), having 2 to 6 carbon atoms (a “C₂-C₆ alkyl”), or having 1 to 4carbon atoms (a “C₁-C₄ alkyl”). Examples of alkyl groups include, butare not limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and thelike.

“Alkylene” as used herein refers to the same residues as alkyl, buthaving bivalency. Particular alkylene groups are those having 1 to 20carbon atoms (a “C₁-C₂₀ alkylene”), having 1 to 10 carbon atoms (a“C₁-C₁₀ alkylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀ alkylene”),having 1 to 6 carbon atoms (a “C₁-C₆ alkylene”), 1 to 5 carbon atoms (a“C₁-C₅ alkylene”), 1 to 4 carbon atoms (a “C₁-C₄ alkylene”) or 1 to 3carbon atoms (a “C₁-C₃ alkylene”). Examples of alkylene include, but arenot limited to, groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), butylene(—CH₂(CH₂)₂CH₂—), isobutylene (—CH₂CH(CH₃)CH₂—), pentylene(—CH₂(CH₂)₃CH₂—), hexylene (—CH₂(CH₂)₄CH₂—), heptylene (—CH₂(CH₂)₅CH₂—),octylene (—CH₂(CH₂)₆CH₂—), and the like.

“Alkenyl” as used herein refers to and includes, unless otherwisestated, an unsaturated linear (i.e., unbranched) or branched univalenthydrocarbon chain or combination thereof, having at least one site ofolefinic unsaturation (i.e., having at least one moiety of the formulaC═C) and having the number of carbon atoms designated (i.e., C₂-C₁₀means two to ten carbon atoms). An alkenyl group may have “cis” or“trans” configurations, or alternatively have “E” or “Z” configurations.Particular alkenyl groups are those having 2 to 20 carbon atoms (a“C₂-C₂₀ alkenyl”), having 6 to 10 carbon atoms (a “C₆-C₀ alkenyl”),having 2 to 8 carbon atoms (a “C₂-C₈ alkenyl”), having 2 to 6 carbonatoms (a “C₂-C₆ alkenyl”), or having 2 to 4 carbon atoms (a “C₂-C₄alkenyl”). Examples of alkenyl group include, but are not limited to,groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl),2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof,for example, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl,hex-3-enyl, and the like.

“Alkenylene” as used herein refers to the same residues as alkenyl, buthaving bivalency. Particular alkylene groups are those having 2 to 20carbon atoms (a “C₂-C₂₀ alkenylene”), having 2 to 10 carbon atoms (a“C₂-C₁₀ alkenylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkenylene”), having 2 to 6 carbon atoms (a “C₂-C₆ alkenylene”), 2 to 4carbon atoms (a “C₂-C₄ alkenylene”) or 2 to 3 carbon atoms (a “C₂-C₃alkenylene”). Examples of alkenylene include, but are not limited to,groups such as ethenylene (or vinylene) (—CH═CH—), propenylene(—CH═CHCH₂—), 1,4-but-1-enylene (—CH═CH—CH₂CH₂—), 1,4-but-2-enylene(—CH₂CH═CHCH₂—), 1,6-hex-1-enylene (—CH═CH—(CH₂)₃CH₂—), and the like.

“Alkynyl” as used herein refers to and includes, unless otherwisestated, an unsaturated linear (i.e., unbranched) or branched univalenthydrocarbon chain or combination thereof, having at least one site ofacetylenic unsaturation (i.e., having at least one moiety of the formulaC≡C) and having the number of carbon atoms designated (i.e., C₂-C₁₀means two to ten carbon atoms). Particular alkynyl groups are thosehaving 2 to 20 carbon atoms (a “C₂-C₂₀ alkynyl”), having 6 to 10 carbonatoms (a “C₆-C₁₀ alkynyl”), having 2 to 8 carbon atoms (a “C₂-C₈alkynyl”), having 2 to 6 carbon atoms (a “C₂-C₆ alkynyl”), or having 2to 4 carbon atoms (a “C₂-C₄ alkynyl”). Examples of alkynyl groupinclude, but are not limited to, groups such as ethynyl (or acetylenyl),prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl,but-3-ynyl, homologs and isomers thereof, and the like.

“Alkynylene” as used herein refers to the same residues as alkynyl, buthaving bivalency. Particular alkylene groups are those having 2 to 20carbon atoms (a “C₂-C₂₀ alkynylene”), having 2 to 10 carbon atoms (a“C₂-C₁₀ alkynylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkynylene”), having 2 to 6 carbon atoms (a “C₂-C₆ alkynylene”), 2 to 4carbon atoms (a “C₂-C₄ alkynylene”) or 2 to 3 carbon atoms (a “C₂-C₃alkynylene”). Examples of alkynylene include, but are not limited to,groups such as ethynylene (or acetylenylene) (—C≡C—), propynylene(—C≡CCH₂—), and the like.

“Cycloalkyl” as used herein refers to and includes, unless otherwisestated, saturated cyclic univalent hydrocarbon structures, having thenumber of carbon atoms designated (i.e., C₃-C₁₀ means three to tencarbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl,or multiple rings, such as adamantyl. A cycloalkyl comprising more thanone ring may be fused, spiro or bridged, or combinations thereof.Particular cycloalkyl groups are those having from 3 to 12 annularcarbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from3 to 8 annular carbon atoms (a “C₃-C₈ cycloalkyl”), having 3 to 6 carbonatoms (a “C₃-C₆ cycloalkyl”), or having from 3 to 4 annular carbon atoms(a “C₃-C₄ cycloalkyl”). Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, norbornyl, and the like.

“Cycloalkylene” as used herein refers to the same residues ascycloalkyl, but having bivalency. Cycloalkylene can consist of one ringor multiple rings which may be fused, spiro or bridged, or combinationsthereof. Particular cycloalkylene groups are those having from 3 to 12annular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbonhaving from 3 to 8 annular carbon atoms (a “C₃-C₈ cycloalkylene”),having 3 to 6 carbon atoms (a “C₃-C₆ cycloalkylene”), or having from 3to 4 annular carbon atoms (a “C₃-C₄ cycloalkylene”). Examples ofcycloalkylene include, but are not limited to, cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene,norbornylene, and the like. A cycloalkylene may attach to the remainingstructures via the same ring carbon atom or different ring carbon atoms.When a cycloalkylene attaches to the remaining structures via twodifferent ring carbon atoms, the connecting bonds may be cis- or trans-to each other. For example, cyclopropylene may include1,1-cyclopropylene and 1,2-cyclopropylene (e.g., cis-1,2-cyclopropyleneor trans-1,2-cyclopropylene), or a mixture thereof.

“Cycloalkenyl” refers to and includes, unless otherwise stated, anunsaturated cyclic non-aromatic univalent hydrocarbon structure, havingat least one site of olefinic unsaturation (i.e., having at least onemoiety of the formula C═C) and having the number of carbon atomsdesignated (i.e., C₂-C₁₀ means two to ten carbon atoms). Cycloalkenylcan consist of one ring, such as cyclohexyl, or multiple rings, such asnorbornenyl. A preferred cycloalkenyl is an unsaturated cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkenyl”). Examples of cycloalkenyl groups include, but are notlimited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,norbornenyl, and the like.

“Cycloalkenylene” as used herein refers to the same residues ascycloalkenyl, but having bivalency.

“Aryl” or “Ar” as used herein refers to an unsaturated aromaticcarbocyclic group having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic. Particular aryl groups are those having from 6 to14 annular carbon atoms (a “C₆-C₁₄ aryl”). An aryl group having morethan one ring where at least one ring is non-aromatic may be connectedto the parent structure at either an aromatic ring position or at anon-aromatic ring position. In one variation, an aryl group having morethan one ring where at least one ring is non-aromatic is connected tothe parent structure at an aromatic ring position.

“Arylene” as used herein refers to the same residues as aryl, but havingbivalency. Particular arylene groups are those having from 6 to 14annular carbon atoms (a “C₆-C₁₄ arylene”).

“Heteroaryl” as used herein refers to an unsaturated aromatic cyclicgroup having from 1 to 14 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic.Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12annular carbon atoms and 1 to 6 annular heteroatoms independentlyselected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independentlyselected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered ringshaving 1 to 5 annular carbon atoms and 1 to 4 annular heteroatomsindependently selected from nitrogen, oxygen and sulfur. In onevariation, particular heteroaryl groups are monocyclic aromatic 5-, 6-or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4annular heteroatoms independently selected from nitrogen, oxygen andsulfur. In another variation, particular heteroaryl groups arepolycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1to 6 annular heteroatoms independently selected from nitrogen, oxygenand sulfur. A heteroaryl group having more than one ring where at leastone ring is non-aromatic may be connected to the parent structure ateither an aromatic ring position or at a non-aromatic ring position. Inone variation, a heteroaryl group having more than one ring where atleast one ring is non-aromatic is connected to the parent structure atan aromatic ring position. A heteroaryl group may be connected to theparent structure at a ring carbon atom or a ring heteroatom.

“Heteroarylene” as used herein refers to the same residues asheteroaryl, but having bivalency.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refersto a saturated or an unsaturated non-aromatic cyclic group having asingle ring or multiple condensed rings, and having from 1 to 14 annularcarbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen,sulfur or oxygen, and the like. A heterocycle comprising more than onering may be fused, bridged or spiro, or any combination thereof. Infused ring systems, one or more of the fused rings can be cycloalkyl,aryl or heteroaryl. The heterocyclyl group may be optionally substitutedindependently with one or more substituents described herein. Particularheterocyclyl groups are 3 to 14-membered rings having 1 to 13 annularcarbon atoms and 1 to 6 annular heteroatoms independently selected fromnitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11annular carbon atoms and 1 to 6 annular heteroatoms independentlyselected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independentlyselected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independentlyselected from nitrogen, oxygen and sulfur, or 3 to 6-membered ringshaving 1 to 5 annular carbon atoms and 1 to 4 annular heteroatomsindependently selected from nitrogen, oxygen and sulfur. In onevariation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-memberedrings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annularcarbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatomsindependently selected from nitrogen, oxygen and sulfur. In anothervariation, heterocyclyl includes polycyclic non-aromatic rings havingfrom 1 to 12 annular carbon atoms and 1 to 6 annular heteroatomsindependently selected from nitrogen, oxygen and sulfur.

“Heterocyclylene” as used herein refers to the same residues asheterocyclyl, but having bivalency.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each hydrogenis replaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Thiocarbonyl” refers to the group C═S.

“Oxo” refers to the moiety ═O.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or5) of the substituents listed for that group in which the substituentsmay be the same of different. In one embodiment, an optionallysubstituted group has one substituent. In another embodiment, anoptionally substituted group has two substituents. In anotherembodiment, an optionally substituted group has three substituents. Inanother embodiment, an optionally substituted group has foursubstituents. In some embodiments, an optionally substituted group has 1to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a primate, human, bovine,horse, feline, canine, or rodent. In one variation, the individual is ahuman.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this invention, beneficial or desired results include, but are notlimited to, one or more of the following: decreasing one more symptomsresulting from the disease, diminishing the extent of the disease,stabilizing the disease (e.g., preventing or delaying the worsening ofthe disease), preventing or delaying the spread of the disease, delayingthe occurrence or recurrence of the disease, delay or slowing theprogression of the disease, ameliorating the disease state, providing aremission (whether partial or total) of the disease, decreasing the doseof one or more other medications required to treat the disease,enhancing effect of another medication, delaying the progression of thedisease, increasing the quality of life, and/or prolonging survival.Also encompassed by “treatment” is a reduction of pathologicalconsequence of fibrosis. The methods of the invention contemplate anyone or more of these aspects of treatment.

As used herein, the term “effective amount” intends such amount of acompound of the invention which should be effective in a giventherapeutic form. As is understood in the art, an effective amount maybe in one or more doses, i.e., a single dose or multiple doses may berequired to achieve the desired treatment endpoint. An effective amountmay be considered in the context of administering one or moretherapeutic agents (e.g., a compound, or pharmaceutically acceptablesalt thereof), and a single agent may be considered to be given in aneffective amount if, in conjunction with one or more other agents, adesirable or beneficial result may be or is achieved. Suitable doses ofany of the co-administered compounds may optionally be lowered due tothe combined action (e.g., additive or synergistic effects) of thecompounds.

A “therapeutically effective amount” refers to an amount of a compoundor salt thereof sufficient to produce a desired therapeutic outcome.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier.

Unit dosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to adrug-containing formulation or fraction thereof in which release of thedrug is not immediate, i.e., with a “controlled release” formulation,administration does not result in immediate release of the drug into anabsorption pool. The term encompasses depot formulations designed togradually release the drug compound over an extended period of time.Controlled release formulations can include a wide variety of drugdelivery systems, generally involving mixing the drug compound withcarriers, polymers or other compounds having the desired releasecharacteristics (e.g., pH-dependent or non-pH-dependent solubility,different degrees of water solubility, and the like) and formulating themixture according to the desired route of delivery (e.g., coatedcapsules, implantable reservoirs, injectable solutions containingbiodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Pharmaceutically acceptable salts can be prepared in situ inthe manufacturing process, or by separately reacting a purified compoundof the invention in its free acid or base form with a suitable organicor inorganic base or acid, respectively, and isolating the salt thusformed during subsequent purification.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

Compounds

In one aspect, provided is a compound of formula (I):

or a salt thereof, wherein:

R¹ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, 3- to 12-membered heterocyclyl, —OR² or —NR^(3a)R^(3b),wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R¹ areindependently optionally substituted by R¹⁰;

R² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, or 3- to 12-membered heterocyclyl, wherein the C₁-C₆ alkyl,C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to12-membered heterocyclyl of R² are independently optionally substitutedby R¹⁰;

R^(3a) and R^(3b) are independently hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-memberedheterocyclyl of R^(3a) and R^(3b) are independently optionallysubstituted by R¹⁰;

-   -   or R^(3a) and R^(3b) are taken together with the nitrogen to        which they are attached to form a 4- to 8-membered heterocyclyl        optionally substituted by R¹⁰;

n is 1 or 2;

m is 0 to 6;

each R⁵, where present, is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl,halogen. —CN, —OR^(5a), —C(O)OR^(5a), —NR^(5a)C(O)R^(5b);—NR^(5c)R^(5d), —C(O)NR^(5c)R^(5d), —SO₂R^(5c), or —SO₂NR^(5c)R^(5d),wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl are independentlyoptionally substituted by R¹⁰;

each R^(5a) and R^(5b) is independently hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-memberedheterocyclyl of R^(5a) and R^(5b) are independently optionallysubstituted by R¹⁰;

each R^(5c) and R^(5d) is independently hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₄ aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-memberedheterocyclyl of R^(5c) and R^(5d) are independently optionallysubstituted by R¹⁰;

-   -   or R^(5c) and R^(5d) are taken together with the nitrogen to        which they are attached to form a 4- to 8-membered heterocyclyl        optionally substituted by R¹⁰;

each R^(5e) is independently C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl,5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, whereinthe C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, and 3- to 12-membered heterocyclyl of R^(5e) areindependently optionally substituted by R¹⁰;

X is C₁-C₃ alkylene optionally substituted by R¹⁰;

p is 0 to 2;

q is 0 to 6;

each R⁷, where present, is independently C₁-C₆ alkyl optionallysubstituted by halogen or —OH, C₃-C₆ cycloalkyl, halogen, —CN, —NO₂,—OR^(7a), or —NR^(7b)R^(7c);

each R^(7a), R^(7b) and R^(7c) is independently hydrogen or C₁-C₃ alkyl;each R⁸, where present, is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl;halogen, oxo or —OR^(8a), wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkylare independently optionally substituted by R¹⁰;

R^(8a) is hydrogen or C₁-C₆ alkyl;

each R⁹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —CN, —OR¹¹, —SR¹¹, —NR¹²R¹³, —NO₂, —C═NH(OR¹¹), —C(O)R¹¹,—OC(O)R¹¹, —C(O)OR¹¹, —C(O)NR¹²R¹³, —NR¹¹C(O)R¹², —NR¹¹C(O)OR¹²,—NR¹¹C(O)NR¹²R¹³, —S(O)R¹¹, —S(O)₂R¹¹, —NR¹¹S(O)R¹², —NR¹¹S(O)₂R¹²,—S(O)NR¹²R¹³, —S(O)₂NR¹²R¹³, —P(O)(OR¹²) (OR¹³), C₃-C₈ cycloalkyl, 3- to12-membered heterocyclyl, 5- to 10-membered heteroaryl, C₆-C₁₄ aryl,wherein each R⁹ is independently optionally substituted by halogen, oxo,—OR¹⁴, —NR¹⁴R¹⁵, —C(O)R¹⁴, —CN, —S(O)R¹⁴, —S(O)₂R¹⁴, —P(O)(OR¹⁴)(OR¹⁵),C₃-C₈ cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-memberedheteroaryl, C₆-C₄ aryl, or C₁-C₆ alkyl optionally substituted by oxo,—OH or halogen;

each R¹⁰ is independently oxo or R⁹;

R¹¹ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5- to 6-membered heteroaryl or3- to 6-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5- to 6-memberedheteroaryl and 3- to 6-membered heterocyclyl are independentlyoptionally substituted by halogen, oxo, —CN, —OR¹⁶, —NR¹⁶R¹⁷,—P(O)(OR¹⁶)(OR⁷), or C₁-C₆ alkyl optionally substituted by halogen, —OHor oxo;

R¹² and R¹³ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5- to 6-memberedheteroaryl or 3- to 6-membered heterocyclyl, wherein the C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5- to6-membered heteroaryl and 3- to 6-membered heterocyclyl areindependently optionally substituted by halogen, oxo, —CN, —OR¹⁶,—NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substituted by halogen, —OH or oxo;

-   -   or R¹² and R¹³ are taken together with the atom to which they        attached to form a 3- to 6-membered heterocyclyl optionally        substituted by halogen, oxo, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl        optionally substituted by halogen, oxo or —OH;

R¹⁴ and R¹⁵ are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo;

-   -   or R¹⁴ and R¹⁵ are taken together with the atom to which they        attached to form a 3- to 6-membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₆ alkyl optionally        substituted by halogen or oxo; and

R¹⁶ and R¹⁷ are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo;

-   -   or R¹⁶ and R¹⁷ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₆ alkyl optionally        substituted by oxo or halogen.

In another aspect is provided is a compound of formula (I-A):

or a salt thereof, wherein:

R¹ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, 3- to 12-membered heterocyclyl, —OR² or —NR^(3a)R^(3b),wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R¹ areindependently optionally substituted by R⁰;

R² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, or 3- to 12-membered heterocyclyl, wherein the C₁-C₆ alkyl,C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to12-membered heterocyclyl of R² are independently optionally substitutedby R¹⁰;

R^(3a) and R^(3b) are independently hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-memberedheterocyclyl of R^(3a) and R^(3b) are independently optionallysubstituted by R¹⁰;

-   -   or R^(3a) and R^(3b) are taken together with the nitrogen to        which they are attached to form a 4- to 8-membered heterocyclyl        optionally substituted by R¹⁰;

n is 1 or 2;

s is 0, 1 or 2, wherein the sum of n and s is 1, 2 or 3;

the ring defined by - - - - - - is present or absent;

m is 0 to 6;

each R⁵, where present, is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl,halogen, —CN, —OR^(5a), —C(O)OR^(5a), —NR^(5a)C(O)R^(5b);—NR^(5c)R^(5d), —C(O)NR^(5c)R^(5d), —SO₂R^(5e), or —SO₂NR^(5c)R^(5d),wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl are independentlyoptionally substituted by R¹⁰;

each R^(5a) and R^(5b) is independently hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-memberedheterocyclyl of R^(5a) and R^(5b) are independently optionallysubstituted by R¹⁰;

each R^(5c) and R^(5d) is independently hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-memberedheterocyclyl of R^(5c) and R^(5d) are independently optionallysubstituted by R¹⁰;

-   -   or R^(5c) and R^(5d) are taken together with the nitrogen to        which they are attached to form a 4- to 8-membered heterocyclyl        optionally substituted by R¹⁰;

each R^(5e) is independently C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl,5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, whereinthe C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, and 3- to 12-membered heterocyclyl of R^(5e) areindependently optionally substituted by R¹⁰;

X is C₁-C₃ alkylene optionally substituted by R¹⁰, —N(R¹¹)—C₁-C₃alkylene optionally substituted by R¹⁰, —C₁-C₃ alkylene-N(R¹¹)—optionally substituted by R¹⁰, —C₁-C₃ alkylene-N(R¹¹)— C₁-C₃ alkylene-optionally substituted by R¹⁰, —O—C₁-C₃ alkylene optionally substitutedby R¹⁰, —C₁-C₃ alkylene-O— optionally substituted by R¹⁰, —C₁-C₃alkylene-O—C₁-C₃ alkylene- optionally substituted by R¹⁰;

Y is C(R^(ya))(R^(yb)) or N(R¹¹);

each of R^(ya) and R^(yb) is independently H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, halogen, —CN, —OR^(5a), —C(O)OR^(5a), —NR^(5a)C(O)R^(5b);—NR^(5c)R^(5d), —C(O)NR^(5c)R^(5d), —SO₂R^(5e), or —SO₂NR^(5c)R^(5d),wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl are independentlyoptionally substituted by R¹⁰;

p is 0 to 2;

q is 0 to 6;

each R⁷, where present, is independently C₁-C₆ alkyl optionallysubstituted by halogen or —OH, C₃-C₆ cycloalkyl, halogen, —CN, —NO₂,—OR^(7a), or —NR^(7b)R^(7c);

each R^(7a), R^(7b) and R^(7c) is independently hydrogen or C₁-C₃ alkyl;

each R^(8a), where present, is independently C₁-C₆ alkyl, C₃-C₆cycloalkyl; halogen, oxo or —OR^(8a), wherein the C₁-C₆ alkyl and C₃-C₆cycloalkyl are independently optionally substituted by R¹⁰;

R^(8a) is hydrogen or C₁-C₆ alkyl;

each R⁹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —CN, —OR¹¹, —SR¹¹, —NR¹²R¹³, —NO₂, —C═NH(OR¹¹), —C(O)R¹¹,—OC(O)R¹¹, —C(O)OR¹¹, —C(O)NR¹²R¹³, —NR¹¹C(O)R¹², —NR¹¹C(O)OR¹²,—NR¹¹C(O)NR¹²R¹³, —S(O)R¹¹, —S(O)₂R¹¹, —NR¹¹S(O)R¹², —NR¹¹S(O)₂R¹²,—S(O)NR¹²R¹³, —S(O)₂NR¹²R¹³, —P(O)(OR¹²) (OR¹³), C₃-C₈ cycloalkyl, 3- to12-membered heterocyclyl, 5- to 10-membered heteroaryl, C₆-C₁₄ aryl,wherein each R⁹ is independently optionally substituted by halogen, oxo,—OR¹⁴, —NR¹⁴R¹⁵, —C(O)R¹⁴, —CN, —S(O)R¹⁴, —S(O)₂R¹⁴, —P(O)(OR¹⁴)(OR¹⁵),C₃-C₈ cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-memberedheteroaryl, C₆-C₄ aryl, or C₁-C₆ alkyl optionally substituted by oxo,—OH or halogen;

each R¹⁰ is independently oxo or R⁹;

R¹¹ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5- to 6-membered heteroaryl or3- to 6-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5- to 6-memberedheteroaryl and 3- to 6-membered heterocyclyl are independentlyoptionally substituted by halogen, oxo, —CN, —OR¹⁶, —NR¹⁶R¹⁷,—P(O)(OR¹⁶)(OR¹⁷), or C₁-C₆ alkyl optionally substituted by halogen, —OHor oxo;

R¹² and R¹³ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5- to 6-memberedheteroaryl or 3- to 6-membered heterocyclyl, wherein the C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5- to6-membered heteroaryl and 3- to 6-membered heterocyclyl areindependently optionally substituted by halogen, oxo, —CN, —OR¹⁶,—NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substituted by halogen, —OH or oxo;

-   -   or R¹² and R¹³ are taken together with the atom to which they        attached to form a 3- to 6-membered heterocyclyl optionally        substituted by halogen, oxo, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl        optionally substituted by halogen, oxo or —OH;

R¹⁴ and R¹⁵ are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo;

-   -   or R¹⁴ and R¹⁵ are taken together with the atom to which they        attached to form a 3- to 6-membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₆ alkyl optionally        substituted by halogen or oxo; and

R¹⁶ and R¹⁷ are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo;

or R¹⁶ and R¹⁷ are taken together with the atom to which they attachedto form a 3-6 membered heterocyclyl optionally substituted by halogen,oxo or C₁-C₆ alkyl optionally substituted by oxo or halogen.

It is understood that when the ring defined by - - - - - - is present,only one such ring is present.

In some embodiments, the compound of the formula (I) is a derivativeof(S)-2-acylaminobutanoic acid, having the formula (Ia):

or a salt thereof, wherein R¹, R⁵, R⁷, R⁸, X, m, n, p and q are asdefined for formula (I).

In some embodiments, the compound of the formula (I) is a derivative of(R)-2-acylaminobutanoic acid, having the formula (Ib):

or a salt thereof, wherein R¹, R⁵, R⁷, R⁸, X, m, n, p and q are asdefined for formula (I).

In some embodiments of the compound of formula (I), (Ia) or (Ib), or asalt thereof, n is 1. In some embodiments, n is 2. In some of theseembodiments, m is 0. In some these embodiments, m is 1. In some theseembodiments, m is 2. In some these embodiments, m is 3. In some theseembodiments, m is 4. In some these embodiments, m is 5. In some theseembodiments, m is 6. In some embodiments, m is 1 or 2.

In some embodiments of the compound of formula (I), (Ia) or (Ib), or asalt thereof, each R⁵, where present, is independently C₁-C₆ alkyloptionally substituted by R¹⁰, C₃-C₆ cycloalkyl optionally substitutedby R⁰, halogen, —CN, —OR^(5a), —C(O)OR^(5a), —NR^(5a)C(O)R^(5b);—NR^(5c)R^(5d), —C(O)NR^(5c)R^(5d), —SO₂R^(5e), or —SO₂NR^(5c)R^(5d). Insome of these embodiments, each R^(5a) and R^(5b) is independentlyhydrogen, C₁-C₆ alkyl optionally substituted by R¹⁰; C₃-C₈ cycloalkyloptionally substituted by R⁰; C₆-C₁₄ aryl optionally substituted by R¹⁰;5- to 10-membered heteroaryl optionally substituted by R¹⁰; or 3- to12-membered heterocyclyl optionally substituted by R¹⁰. In some of theseembodiments, each R^(5c) and R^(5d) is independently hydrogen, C₁-C₆alkyl optionally substituted by R¹⁰; C₃-C₈ cycloalkyl optionallysubstituted by R¹⁰; C₆-C₄ aryl optionally substituted by R¹⁰; 5- to10-membered heteroaryl optionally substituted by R¹⁰; or 3- to12-membered heterocyclyl optionally substituted by R¹⁰; or R^(5c) andR^(5d) are taken together with the nitrogen to which they are attachedto form a 4- to 8-membered heterocyclyl optionally substituted by R¹⁰.In some of these embodiments, R^(5e) is C₁-C₆ alkyl optionallysubstituted by R¹⁰; C₃-C₈ cycloalkyl optionally substituted by R¹⁰;C₆-C₁₄ aryl optionally substituted by R⁰; 5- to 10-membered heteroaryloptionally substituted by R¹⁰; or 3- to 12-membered heterocyclyloptionally substituted by R¹⁰.

In some embodiments of the compound of formula (I), where n is 1 and mis 0, the compound is of the formula (II):

or a salt thereof, wherein R¹, R⁷, R⁸, X, p and q are as defined forformula (I).

In some embodiments, the compound of the formula (II) is a derivative of(S)-2-acylaminobutanoic acid, having the formula (IIa):

or a salt thereof, wherein R¹, R⁷, R⁸, X, p and q are as defined forformula (I) or (II).

In some embodiments, the compound of the formula (II) is a derivative of(R)-2-acylaminobutanoic acid, having the formula (IIb):

or a salt thereof, wherein R¹, R⁷, R⁸, X, p and q are as defined forformula (I) or (II).

In some embodiments of the compound of formula (I), where n is 2 and mis 0, the compound is of the formula (III):

or a salt thereof, wherein R¹, R⁷, R⁸, X, p and q are as defined forformula (I).

In some embodiments, the compound of the formula (III) is a derivativeof (S)-2-acylaminobutanoic acid, having the formula (IIIa):

or a salt thereof, wherein R¹, R⁷, R⁸, X, p and q are as defined forformula (I) or (III).

In some embodiments, the compound of the formula (III) is a derivativeof (R)-2-acylaminobutanoic acid, having the formula (IIIb):

or a salt thereof, wherein R¹, R⁷, R⁸, X, p and q are as defined forformula (I) or (III).

In some embodiments of the compound of formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa) or (IIIb), or a salt thereof, X is C₁-C₃alkylene optionally substituted by R¹⁰. In some embodiments, X is C₁-C₂alkylene optionally substituted by R¹⁰. In some embodiments, X ismethylene optionally substituted by 1 or 2 groups selected from R¹⁰. Insome embodiments, X is ethylene optionally substituted by 1 to 4 groupsselected from R¹⁰. In some embodiments, X is propylene optionallysubstituted by 1 or 5 groups selected from R¹⁰. In some embodiments, Xis methylene. In some embodiments, X is ethylene. In some embodiments, Xis propylene.

It is intended and understood that each and every variation of n, m andR⁵ described herein, may be combined with each and every variation of Xdescribed herein, the same as if each and every combination isindividually and specifically described. For example, in someembodiments of the compound of formula (I), (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa) or (IIIb), or a salt thereof, n is 1, m is 0, and Xis ethylene. In some embodiments of the compound of formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa) or (IIIb), or a salt thereof, nis 2, m is 0, and X is ethylene.

In some embodiments of the compound of formula (I), where n is 1, m is0, and X is ethylene, the compound is of the formula (IV):

or a salt thereof, wherein R¹, R⁷, R⁸, p and q are as defined forformula (I) or (II).

In some embodiments, the compound of the formula (IV) is of the formula(IVa):

or a salt thereof, wherein R¹, R⁷, R⁸, p and q are as defined forformula (I) or (II).

In some embodiments, the compound of the formula (IV) is of the formula(IVb):

or a salt thereof, wherein R¹, R⁷, R⁸, p and q are as defined forformula (I) or (II).

In some embodiments, the compound of the formula (IV) is of the formula(IVc):

or a salt thereof, wherein R¹, R⁷, R⁸, p and q are as defined forformula (I) or (II).

In some embodiments, the compound of the formula (IV) is of the formula(IVd):

or a salt thereof, wherein R¹, R⁷, R⁸, p and q are as defined forformula (I) or (II).

In some embodiments of the compound of formula (I), where n is 2, m is0, and X is ethylene, the compound is of the formula (V):

or a salt thereof, wherein R¹, R⁷, R⁸, p and q are as defined forformula (I) or (III).

In some embodiments, the compound of the formula (V) is of the formula(Va):

or a salt thereof, wherein R¹, R⁷, R⁸, p and q are as defined forformula (I) or (III).

In some embodiments, the compound of the formula (V) is of the formula(Vb):

or a salt thereof, wherein R¹, R⁷, R⁸, p and q are as defined forformula (I) or (III).

In some embodiments of the compound of formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd),(V), (Va) or (Vb), or a salt thereof, R¹ is C₁-C₆ alkyl optionallysubstituted by R¹⁰; C₃-C₈ cycloalkyl optionally substituted by R¹⁰;C₆-C₁₄ aryl optionally substituted by R¹⁰; 5- to 10-membered heteroaryloptionally substituted by R¹⁰; 3- to 12-membered heterocyclyl optionallysubstituted by R¹⁰; —OR²; or —NR^(3a)R^(3b).

In some embodiments, R¹ is a C₁-C₆ alkyl (e.g., t-butyl) optionallysubstituted by R¹⁰.

In some embodiments. R¹ is —OR² or —NR^(3a)R^(3b).

In some embodiments, R¹ is —OR². In some embodiments, R² is C₁-C₆ alkyl(e.g., t-butyl).

In some embodiments, R¹ is —NR^(3a)R^(3b). In some embodiments, R¹ is a4- to 8-membered heterocyclyl optionally substituted by R¹⁰ formed byR^(3a) and R^(3b) taken together with the nitrogen to which they areattached.

In some embodiments, R¹ is C₃-C₈ cycloalkyl (e.g., cyclohexyl)optionally substituted by R¹⁰. In some embodiments, R¹ is4,4-difluorocyclohexyl.

In some embodiments, R¹ is C₆-C₁₄ aryl optionally substituted by R¹⁰. Insome embodiments, R¹ is phenyl optionally substituted by R¹⁰.

In some embodiments, R¹ is 5- or 10-membered heteroaryl optionallysubstituted by R¹⁰. In some embodiments, R¹ is 5- to 6-memberedmonocyclic heteroaryl optionally substituted by R¹⁰. In someembodiments, R¹ is pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl)optionally substituted by R¹⁰. In some embodiments, R¹ is 8- to10-membered bicyclic heteroaryl optionally substituted by R¹⁰. In someembodiments, R¹ is indazolyl (e.g., 4-indozyl, 5-indozyl, 6-indozyl or7-indozyl) optionally substituted by R¹⁰.

In some embodiments, R¹ is 3- to 12-membered heterocyclyl optionallysubstituted by R¹⁰. In some embodiments, R¹ is piperidinyl (e.g.,piperidin-4-yl) optionally substituted by R¹⁰. In some embodiments, R¹is 1-cyclopropylpiperidin-4-yl. In some embodiments, R¹ istetrahydropyranyl (e.g., tetrahydropyran-4-yl) optionally substituted byR¹⁰. In some embodiments, R¹ is 4-methyltetrahydropyran-4-yl.

It is intended and understood that each and every variation of R¹described herein, may be combined with each and every variation of X, n,m and R⁵ described herein, the same as if each and every combination isindividually and specifically described. For example, in someembodiments of the compound of formula (I), (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V),(Va) or (Vb), or a salt thereof, R¹ is selected from the groupconsisting of:

In the compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or (Vb), ora salt thereof, the 5,6,7,8-tetrahydro-1,8-naphthyridine ring may beunsubstituted or substituted. In some embodiments, p is 0. In someembodiments, q is 0. In some embodiments, p and q are 0. In someembodiments, p is 1 or 2, and each R⁷ is independently C₁-C₆ alkyloptionally substituted by halogen or —OH, C₃-C₆ cycloalkyl, halogen,—CN, —NO₂, —OR^(7a), or —NR^(7b)R^(7c); where each R^(7a), R^(7b) andR^(7c) is independently hydrogen or C₁-C₃ alkyl. In some embodiments, R⁷is —CH₃, —CHF₂, —CH₂F, —CF₃, or —CH₂OH. In some embodiments, q is 1 to6, and each R⁸ is independently C₁-C₆ alkyl optionally substituted byR¹⁰, C₃-C₆ cycloalkyl optionally substituted by R¹⁰, halogen, oxo or—OR^(8a). In some embodiments, R⁸ is —OR^(8a) where R^(8a) is hydrogenor C₁-C₆ alkyl. In some embodiments, R^(8a) is hydrogen.

In some embodiments, each optional substituent R⁹ is independently C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR¹¹, —SR¹¹,—NR¹²R¹³, —NO₂, —C═NH(OR¹¹), —C(O)R¹¹, —OC(O)R¹¹, —C(O)OR¹¹,—C(O)NR¹²R¹³, —NR¹¹C(O)R¹², —NR¹¹C(O)OR¹², —NR¹¹C(O)NR¹²R¹³, —S(O)R¹¹,—S(O)₂R¹¹, —NR¹¹S(O)R¹², —NR¹¹S(O)₂R¹², —S(O)NR¹²R¹³, —S(O)₂NR¹²R¹³,—P(O)(OR¹²) (OR¹³), C₃-C₈ cycloalkyl, 3- to 12-membered heterocyclyl, 5-to 10-membered heteroaryl or C₆-C₁₄ aryl, wherein each R⁹ isindependently optionally substituted by halogen, oxo, —OR¹⁴, —NR¹⁴R¹⁵,—C(O)R¹⁴, —CN, —S(O)R¹⁴, —S(O)₂R¹⁴, —P(O)(OR¹⁴)(OR⁵), C₃-C₈ cycloalkyl,3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C₆-C₁₄aryl, or C₁-C₆ alkyl optionally substituted by oxo, —OH or halogen.

In some embodiments, R⁹ is independently C₁-C₆ alkyl, halogen, —CN,—OR¹¹, —NR¹²R¹³, —C(O)R¹¹, C₃-C₈ cycloalkyl, 3- to 12-memberedheterocyclyl, 5- to 10-membered heteroaryl or C₆-C₄ aryl, wherein eachR⁹ is independently optionally substituted by halogen, oxo, —OR¹⁴,—NR¹⁴R¹⁵, —C(O)R¹⁴, —CN, C₃-C₈ cycloalkyl, 3- to 12-memberedheterocyclyl, 5- to 10-membered heteroaryl, C₆-C₁₄ aryl, or C₁-C₆ alkyloptionally substituted by oxo, —OH or halogen. In some embodiments, R⁹is independently selected from F, Cl, —CN, methyl, —CHF₂, —CF₃,cyclopropylmethyl, tert-butyl, cyclopropyl and phenyl. In someembodiments, R⁹ is independently F, Cl or —CN. In some embodiments, R⁹is independently methyl, —CHF₂, —CF₃, cyclopropylmethyl, tert-butyl orcyclopropyl. In some embodiments, R⁹ is independently phenyl optionallysubstituted by halogen or C₁-C₆ alkyl. In some embodiments, R⁹ is 5- to10-membered heteroaryl optionally substituted by C₁-C₆ alkyl. In someembodiments, R⁹ is 3,5-dimethylpyrazol-1-yl. In some embodiments, R⁹ isindependently 3- to 12-membered heterocyclyl optionally substituted byoxo or C₁-C₆ alkyl.

In some embodiments, R⁹ is morpholin-4-yl.

In some embodiments. R¹⁰ is independently oxo or any variation detailedherein for R⁹. In some embodiments, R¹⁰ is independently oxo, C₁-C₆alkyl, halogen, —CN, —OR¹¹, —NR¹²R¹³, —C(O)R¹¹, C₃-C_(x) cycloalkyl, 3-to 12-membered heterocyclyl, 5- to 10-membered heteroaryl or C₆-C₄ aryl,wherein each R⁹ is independently optionally substituted by halogen, oxo,—OR¹⁴, —NR¹⁴R¹⁵, —C(O)R¹⁴, —CN, C₃-C₈ cycloalkyl, 3- to 12-memberedheterocyclyl, 5- to 10-membered heteroaryl, C₆-C₁₄ aryl, or C₁-C₆ alkyloptionally substituted by oxo, —OH or halogen. In some embodiments, R¹⁰is independently selected from oxo, F, Cl, —CN, methyl, —CHF₂, —CF₃,cyclopropylmethyl, tert-butyl, cyclopropyl and phenyl. In someembodiments, R¹⁰ is independently phenyl optionally substituted byhalogen or C₁-C₆ alkyl. In some embodiments, R¹⁰ is 5- to 10-memberedheteroaryl optionally substituted by C₁-C₆ alkyl. In some embodiments,R¹⁰ is 3,5-dimethylpyrazol-1-yl. In some embodiments, R¹⁰ isindependently 3- to 12-membered heterocyclyl optionally substituted byoxo or C₁-C₆ alkyl. In some embodiments, R¹⁰ is morpholin-4-yl.

In some embodiments, R¹¹, R¹² and R¹³ are each independently hydrogen orC₁-C₆ alkyl. In some embodiments, R¹¹ is hydrogen. In some embodiments.R¹² and R¹³ are each hydrogen.

In some embodiments, R¹⁴ and R¹⁵ are each independently hydrogen orC₁-C₆ alkyl.

In one variation is provided a compound of the formula (I), or a saltthereof, wherein the carbon bearing the CO₂H and NHC(O)R¹ moieties is inthe “S” configuration. In another variation is provided a compound ofthe formula (I), or a salt thereof, wherein the carbon bearing the CO₂Hand NHC(O)R moieties is in the “R” configuration. In one variation isprovided a compound of the formula (I), or a salt thereof, wherein thecarbon bearing the X moiety is in the “S” configuration. In anothervariation is provided a compound of the formula (I), or a salt thereof,wherein the carbon bearing the X moiety is in the “R” configuration. Inone aspect of formula (I), the carbon bearing the CO₂H and NHC(O)R¹moieties is in the “S” configuration and the carbon bearing the X moietyis in the “S” configuration. In one aspect of formula (I), the carbonbearing the CO₂H and NHC(O)R¹ moieties is in the “S” configuration andthe carbon bearing the X moiety is in the “R” configuration. In oneaspect of formula (I), the carbon bearing the CO₂H and NHC(O)R¹ moietiesis in the “R” configuration and the carbon bearing the X moiety is inthe “S” configuration. In one aspect of formula (I), the carbon bearingthe CO₂H and NHC(O)R¹ moieties is in the “R” configuration and thecarbon bearing the X moiety is in the “R” configuration. It isunderstood that the stereochemistry described is equally applicable toand described for other compounds detailed herein, such as compounds ofthe formula (I-A) and compounds in the associated compound tables, suchas Table 1 and Table 1-A.

Representative compounds are listed in Table 1.

TABLE 1 Compound No. Structure Chemical Name ¹ 1

2-pivalamido-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 1a(S)-2-pivalamido-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 1b(S)-2-pivalamido-4-((S)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 1c(R)-2-pivalamido-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 1d(R)-2-pivalamido-4-((S)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 2

2-((tert-butoxycarbonyl)amino)-4-(3- (2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 2a(S)-2-((tert-butoxycarbonyl)amino)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 2b(S)-2-((tert-butoxycarbonyl)amino)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 2c(R)-2-((tert-butoxycarbonyl)amino)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 2d(R)-2-((tert-butoxycarbonyl)amino)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 3

2-benzamido-4-(3-(2-(5,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 3a(S)-2-benzamido-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 3b(S)-2-benzamido-4-((S)-3-2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 3c(R)-2-benzamido-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 3d(R)-2-benzamido-4-((S)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 4

2-(2,6-dimethylbenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 4a(S)-2-(2,6-dimethylbenzamido)-4-((R)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 4b(S)-2-(2,6-dimethylbenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 4c(R)-2-(2,6-dimethylbenzamido)-4-((R)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 4d(R)-2-(2,6-dimethylbenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 5

2-(2-chloro-3-fluorobenzamido)-4-(3- (2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 5a(S)-2-(2-chloro-3-fluorobenzamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 5b(S)-2-(2-chloro-3-fluorobenzamido)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 5c(R)-2-(2-chloro-3-fluorobenzamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 5d(R)-2-(2-chloro-3-fluorobenzamido)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 6

6a (S)-2-(2,6-dichlorobenzamido)-4-((R)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 6b(S)-2-(2,6-dichlorobenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 6c(R)-2-(2,6-dichlorobenzamido)-4-((R)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 6d(R)-2-(2,6-dichlorobenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 7

2-(2,6-dichloro-4-cyanobenzamido)-4- (3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 7a(S)-2-(2,6-dichloro-4- cyanobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 7b(S)-2-(2,6-dichloro-4- cyanobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 7c(R)-2-(2,6-dichloro-4- cyanobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 7d(R)-2-(2,6-dichloro-4- cyanobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 8

4-(3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(2- (trifluoromethyl)benzamido)butanoic acid 8a(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(2-(trifluoromethyl)benzamido)butanoic acid 8b(S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(2-(trifluoromethyl)benzamido)butanoic acid 8c(R)-4-(R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(2-(trifluoromethyl)benzamido)butanoic acid 8d(R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(2-(trifluoromethyl)benzamido)butanoic acid 9

4-(3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3- (trifluoromethyl)benzamido)butanoic acid 9a(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(3-(trifluoromethyl)benzamido)butanoic acid 9b(S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(3-(trifluoromethyl)benzamido)butanoic acid 9c(R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(3-(trifluoromethyl)benzamido)butanoic acid 9d(R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(3-(trifluoromethyl)benzamido)butanoic acid 10

4-(3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(4- (trifluoromethyl)benzamido)butanoic acid 10a(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(4-(trifluoromethyl)benzamido)butanoic acid 10b(S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(4-(trifluoromethyl)benzamido)butanoic acid 10c(R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(4-trifluoromethyl)benzamido)butanoic acid 10d(R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)-2-(4-(trifluoromethyl)benzamido)butanoic acid 11

2-(2,6-dichlorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 11a(S)-2-(2,6-dichlorobenzamido)-4-((R)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 11b(S)-2-(2,6-dichlorobenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 11c(R)-2-(2,6-dichlorobenzamido)-4-((R)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- 11dyl)butanoic acid 11d(R)-2-(2,6-dichlorobenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 12

2-(3-(3,5-dimethyl-1H-pyrazol-1- yl)benzamido)-4-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)piperidin-1-yl)butanoic acid 12a(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1- yl)benzamido)-4-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)piperidin-1-yl)butanoic acid 12b(R)-2-(3-(3,5-dimethyl-1H-pyrazol-1- yl)benzamido)-4-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)piperidin-1-yl)butanoic acid 13

2-(3-(3,5-dimethyl-1H-pyrazol-1- yl)benzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid13a (S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 13b(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1- yl)benzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid13c (R)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 13d(R)-2-(3-(3,5-dimethyl-1H-pyrazol-1- yl)benzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 14

2-(2-morpholinobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 14a(S)-2-(2-morpholinobenzamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 14b(S)-2-(2-morpholinobenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 14c(S)-(2-morpholinobenzamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 14d(R)-2-(2-morpholinobenzamido)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 15

2-(3-morpholinobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 15a(S)-2-(3-morpholinobenzamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 15bS)-2-(3-morpholinobenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 15c(R)-2-(3-morpholinobenzamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 15d(R)-2-(3-morpholinobenzamido)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 16

2-(4-morpholinobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidinal-yl)butanoic acid 16a(S)-2-(4-morpholinobenzamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 16b(S)-2-(4-morpholinobenzamido)-4-((S)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 16c(R)-2-(4-morpholinobenzamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 16d(R)-2-(4-morpholinobenzamido)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 17

2-(picolinamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 17a(S)-2-(picolinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 17b(S)-2-(picolinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 17c(R)-2-(picolinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 17d(R)-2-(picolinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 18

2-(isonicotinamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 18a(S)-2-(isonicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 18b(S)-2-(isonicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 18c(R)-2-isonicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 18d(R)-2-(isonicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 19

2-(nicotinamido)-4-(3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 19a(S)-2-(nicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 19b(S)-2-(nicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 19c(R)-2-(nicotinamido)-4-(R)-3-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 19d(R)-2-(nicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 20

2-(3,5-dichloroisonicotinamido)-4-(3- (2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 20a(S)-2-(3,5-dichloroisonicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 20b (S)-2-(3,5-dichloroisonicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 20c (R)-2-(3,5-dichloroisonicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 20d (R)-2-(3,5-dichloroisonicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 21

2-(4,4-difluorocyclohexane-1- carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid21a (S)-2-(4,4-difluorocyclohexane-1- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid21b (S)-2-(4,4-difluorocyclohexane-1- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid21c (R)-2-(4,4-difluorocyclohexane-1- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid21d (R)-2-(4,4-difluorocyclohexane-1- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 22

2-(4-methyltetrahydro-2H-pyran-4- carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid22a (S)-2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 22b(S)-2-(4-methyltetrahydro-2H-pyran-4- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid22c (R)-2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 22d(R)-2-(4-methyltetrahydro-2H-pyran-4- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 23

2-(1-cyclopropylpiperidine-4- carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid23a (S)-2-(1-cyclopropylpiperidine-4- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid23b (S)-2-(1-cyclopropylpiperidine-4- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid23c (R)-2-(1-cyclopropylpiperidine-4- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid23d (R)-2-(1-cyclopropylpiperidine-4- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 24

2-(1-methyl-1H-indazole-6- carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid24a (S)-2-(1-methyl-1H-indazole-6- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid24b (S)-2-(1-methyl-1H-indazole-6- carboxamido)-4-((s)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid24c (r)-2-(1-methyl-1H-indazole-6- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid24d (r)-2-(1-methyl-1H-indazole-6- carboxamido)-4-((s)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 25

2-(1-methyl-1H-indazole-5- carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid25a (S)-2-(1-methyl-1H-indazole-5- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid25b (S)-2-(1-methyl-1H-indazole-5- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid25c (R)-2-(1-methyl-1H-indazole-5- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid25d (R)-2-(1-methyl-1H-indazole-5- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 26

2-(1H-indazole-7-carboxamido)-4-(3- (2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 26a(S)-2-(1H-indazole-7-carboxamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 26b(S)-2-(1H-indazole-7-carboxamido)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 26c(R)-2-(1H-indazole-7-carboxamido)-4- ((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 26d(R)-2-(1H-indazole-7-carboxamido)-4- ((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 27

2-(1-methyl-1H-indazole-4- carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid27a (S)-2-(1-methyl-1H-indazole-4- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid27b (S)-2-(1-methyl-1H-indazole-4- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid27c (R)-2-(1-methyl-1H-indazole-4- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid27d (R)-2-(1-methyl-1H-indazole-4- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 28

2-(1-methyl-1H-indazole-7- carboxamido)-4-(3-(2,5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid28a (S)-2-(1-methyl-1H-indazole-7- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid28b (S)-2-(1-methyl-1H-indazole-7- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid28c (R)-2-(1-methyl-1H-indazole-7- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid28d (R)-2-(1-methyl-1H-indazole-7- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid 29

2-(1-(difluoromethyl)-1H-indazole-6- carboxamido-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid29a (S)-2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 29b(S)-2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-((S)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 29c(R)-2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 29d(R)-2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-((S)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 30

2-(1-(difluoromethyl)-1H-indazole-5- carboxamido)-4-(3-(2,5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid30a (S)-2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 30b(S)-2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-((S)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 30c(R)-2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 30d(R)-2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-((S)-3-(2-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid 31

2-(benzo[d]oxazole-5-carboxamido)-4- (3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid 31a(S)-2-(benzo[d]oxazole-5- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid31b (S)-2-(benzo[d]oxazole-5- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid31c (R)-2-(benzo[d]oxazole-5- carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid31d (R)-2-(benzo[d]oxazole-5- carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid ¹Chemical names are generated using the ChemBioDraw® Ultra version14.0.0.117 software.

Additional representative compounds are listed in Table 1-A.

Compound No. Structure 32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

In some embodiments, provided is a compound selected from Compound Nos.1-31 in Table 1, or a stereoisomer thereof (including a mixture of twoor more stereoisomers thereof), or a salt thereof. In some embodiments,provided is a compound selected from Compound Nos. 1-147, or astereoisomer thereof (including a mixture of two or more stereoisomersthereof), or a salt thereof. In some embodiments, the compound isselected from the group consisting of Compound Nos 1a, 1b, 1c, 1d, 2a,2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, 4d, 5a, 5b, 5c, 5d, 6a, 6b, 6c,6d, 7a, 7b, 7c, 7d, 8a, 8b, 8c, 8d, 9a, 9b, 9c, 9d, 10a, 10b, 10c, 10d,11a, 11b, 11c, 11d, 12a, 12b, 13a, 13b, 13c, 13d, 14a, 14b, 14c, 14d,15a, 15b, 15c, 15d, 16a, 16b, 16c, 16d, 17a, 17b, 17c, 17d, 18a, 18b,18c, 18d, 19a, 19b, 19c, 19d, 20a, 20b, 20c, 20d, 21a, 21b, 21c, 21d,22a, 22b, 22c, 22d, 23a, 23b, 23c, 23d, 24a, 24b, 24c, 24d, 25a, 25b,25c, 25d, 26a, 26b, 26c, 26d, 27a, 27b, 27c, 27d, 28a, 28b, 28c, 28d,29a, 29b, 29c, 29d, 30a, 30b, 30c, 30d, 31a, 3 b, 31c and 31d, or a saltthereof.

In some embodiments, the compound is selected from the group consistingof one or more of Compound Nos. 1-31 in Table 1, or a stereoisomerthereof (including a mixture of two or more stereoisomers thereof), or asalt thereof. In some embodiments, the compound is selected from thegroup consisting of one or more of Compound Nos 1a, 1b, 1c, 1d, 2a, 2b,2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, 4d, 5a, 5b, 5c, 5d, 6a, 6b, 6c, 6d,7a, 7b, 7c, 7d, 8a, 8b, 8c, 8d, 9a, 9b, 9c, 9d, 10a, 10b, 10c, 10d, 11a,11b, 11c, 11d, 12a, 12b, 13a, 13b, 13c, 13d, 14a, 14b, 14c, 14d, 15a,15b, 15c, 15d, 16a, 16b, 16c, 16d, 17a, 17b, 17c, 17d, 18a, 18b, 18c,18d, 19a, 19b, 19c, 19d, 20a, 20b, 20c, 20d, 21a, 21b, 21c, 21d, 22a,22b, 22c, 22d, 23a, 23b, 23c, 23d, 24a, 24b, 24c, 24d, 25a, 25b, 25c,25d, 26a, 26b, 26c, 26d, 27a, 27b, 27c, 27d, 28a, 28b, 28c, 28d, 29a,29b, 29c, 29d, 30a, 30b, 30c, 30d, 31a, 31b, 31c and 31d, or a saltthereof.

In some embodiments, provided is a compound selected from Compound Nos.32-147 in Table 1-A, or a stereoisomer thereof (including a mixture oftwo or more stereoisomers thereof), or a salt thereof.

The invention also includes all salts of compounds referred to herein,such as pharmaceutically acceptable salts. The invention also includesany or all of the stereochemical forms, including any enantiomeric ordiastereomeric forms, and any tautomers or other forms of the compoundsdescribed. Unless stereochemistry is explicitly indicated in a chemicalstructure or name, the structure or name is intended to embrace allpossible stereoisomers of a compound depicted. In addition, where aspecific stereochemical form is depicted, it is understood that otherstereochemical forms are also embraced by the invention. All forms ofthe compounds are also embraced by the invention, such as crystalline ornon-crystalline forms of the compounds. It is also understood thatprodrugs, solvates and metabolites of the compounds are embraced by thisdisclosure. Compositions comprising a compound of the invention are alsointended, such as a composition of substantially pure compound,including a specific stereochemical form thereof. Compositionscomprising a mixture of compounds of the invention in any ratio are alsoembraced by the invention, including mixtures of two or morestereochemical forms of a compound of the invention in any ratio, suchthat racemic, non-racemic, enantioenriched and scalemic mixtures of acompound are embraced.

Compounds described herein are αvβ6 integrin inhibitors. In someinstances, it is desirable for the compound to inhibit other integrinsin addition to αvβ6 integrin. In some embodiments, the compound inhibitsαvβ6 integrin and one or more of αvβ1, αvβ3, αvβ5, α2β1, α3β1, α6β1integrin, α7β1 and α11β1. In some embodiments, the compound inhibitsαvβ6 integrin and αvβ1 integrin. In some embodiments, the compoundinhibits αvβ6 integrin, αvβ3 integrin and αvβ5 integrin. In someembodiments, the compound inhibits αvβ6 integrin and α2β1 integrin. Insome embodiments, the compound inhibits αvβ6 integrin, α2β1 integrin andα3β1 integrin. In some embodiments, the compound inhibits αvβ6 integrinand α6β1 integrin. In some embodiments, the compound inhibits αvβ6integrin and α7β1 integrin. In some embodiments, the compound inhibitsαvβ6 integrin and α11β1 integrin.

In some instances, it is desirable to avoid inhibition of otherintegrins. In some embodiments, the compound is a selective αvβ6integrin inhibitor. In some embodiments, the compound does not inhibitsubstantially α4β1, αvβ8 and/or α2β3 integrin. In some embodiments, thecompound inhibits αvβ6 integrin but does not inhibit substantially α4β1integrin. In some embodiments, the compound inhibits αvβ6 integrin butdoes not inhibit substantially αvβ8 integrin. In some embodiments, thecompound inhibits αvβ6 integrin but does not inhibit substantially α2β3integrin. In some embodiments, the compound inhibits αvβ6 integrin butdoes not inhibit substantially the αvβ8 integrin and the α4β1 integrin.

The invention also intends isotopically-labeled and/orisotopically-enriched forms of compounds described herein. The compoundsherein may contain unnatural proportions of atomic isotopes at one ormore of the atoms that constitute such compounds. In some embodiments,the compound is isotopically-labeled, such as an isotopically-labeledcompound of the formula (I) or variations thereof described herein,where one or more atoms are replaced by an isotope of the same element.Exemplary isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C ¹³N, ¹⁵O,¹⁷O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl. Incorporation of heavier isotopes such asdeuterium (²H) can afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life,or reduced dosage requirements and, hence may be preferred in someinstances.

Isotopically-labeled compounds of the present invention can generally beprepared by standard methods and techniques known to those skilled inthe art or by procedures similar to those described in the accompanyingExamples substituting appropriate isotopically-labeled reagents in placeof the corresponding non-labeled reagent.

The invention also includes any or all metabolites of any of thecompounds described. The metabolites may include any chemical speciesgenerated by a biotransformation of any of the compounds described, suchas intermediates and products of metabolism of the compound.

Articles of manufacture comprising a compound of the invention, or asalt or solvate thereof, in a suitable container are provided. Thecontainer may be a vial, jar, ampoule, preloaded syringe, i.v. bag, andthe like.

Preferably, the compounds detailed herein are orally bioavailable.However, the compounds may also be formulated for parenteral (e.g.,intravenous) administration.

One or several compounds described herein can be used in the preparationof a medicament by combining the compound or compounds as an activeingredient with a pharmacologically acceptable carrier, which are knownin the art. Depending on the therapeutic form of the medication, thecarrier may be in various forms.

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to the formulae herein.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g., a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization, and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

Solvates and/or polymorphs of a compound provided herein or apharmaceutically acceptable salt thereof are also contemplated. Solvatescontain either stoichiometric or non-stoichiometric amounts of asolvent, and are often formed during the process of crystallization.Hydrates are formed when the solvent is water, or alcoholates are formedwhen the solvent is alcohol. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound.Polymorphs usually have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability, and/or solubility. Various factorssuch as the recrystallization solvent, rate of crystallization, andstorage temperature may cause a single crystal form to dominate.

Compounds of the formula (I) can be prepared according to Scheme 1,wherein R¹, R⁵, R⁷, R⁸, X, m, n, p and q are as defined for formula (I),or any applicable variations detailed herein; P⁰ and P¹ areindependently an amine protecting group, (e.g., t-butoxycarbonyl (Boc));P² is a carboxylic acid protecting group (e.g., ethyl); and Lv is aleaving group (e.g., OH, O-acyl, OAt, OBt, Cl, 1-imidazolyl, and thelike).

Reduction (e.g., catalytic hydrogenation) of 1,8-naphthyridine compound(G), for example, using H₂ over palladium hydroxide in methanol, givestetrahydro-1,8-naphthyridine compound (F), which is deprotected to givecompound (E). Reductive alkylation of compound (E) with aldehyde (D) (aprotected 2-amino-4-oxobutanoic acid) produces intermediate compound(C), which is deprotected to give amine compound (B). Coupling of aminecompound (B) with activated carbonyl compound R¹C(O)-Lv givesintermediate compound (A). Deprotection of the carboxylic acid (e.g.,hydrolysis) provides a compound of formula (I).

It is understood that the schemes above may be modified to arrive atvarious compounds of the invention by selection of appropriate reagentsand starting materials. It is also understood that where protection ofcertain active or incompatible groups (e.g., an amine or a carboxylicacid) is required, the formulae in Scheme 1 intend and include compoundswhere such active or incompatible groups are in appropriate protectedforms. For a general description of protecting groups and their use, seeP. G. M. Wuts and T. W. Greene, Greene's Protective Groups in OrganicSynthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

An exemplary embodiment of the preparative method in Scheme 1 is shownin Scheme 1a. In some embodiments, R¹ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, or 3- to 12-memberedheterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5-to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R¹ areindependently optionally substituted by R¹⁰.

Provided is a method for preparing a compound of formula (I), or a saltthereof, comprising performing one or more steps of Scheme 1 or Scheme1a.

Pharmaceutical Compositions and Formulations

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. In onevariation, “substantially pure” intends a composition that contains nomore than 35% impurity, wherein the impurity denotes a compound otherthan the compound comprising the majority of the composition or a saltthereof. For example, a composition of a substantially pure compoundselected from a compound of Table 1 intends a composition that containsno more than 35% impurity, wherein the impurity denotes a compound otherthan the compound or a salt thereof. In one variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains no more than 25% impurity. In another variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 20% impurity. In stillanother variation, a composition of substantially pure compound or asalt thereof is provided wherein the composition contains or no morethan 10% impurity. In a further variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains or no more than 5% impurity. In another variation,a composition of substantially pure compound or a salt thereof isprovided wherein the composition contains or no more than 3% impurity.In still another variation, a composition of substantially pure compoundor a salt thereof is provided wherein the composition contains or nomore than 1% impurity. In a further variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains or no more than 0.5% impurity. In yet othervariations, a composition of substantially pure compound means that thecomposition contains no more than 15% or preferably no more than 10% ormore preferably no more than 5% or even more preferably no more than 3%and most preferably no more than 1% impurity, which impurity may be thecompound in a different stereochemical form. For instance, a compositionof substantially pure (S) compound means that the composition containsno more than 15% or no more than 10% or no more than 5% or no more than3% or no more than 1%/0 of the (R) form of the compound.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual such as a human. In anothervariation, compositions are provided containing a compound insubstantially pure form. In another variation, the invention embracespharmaceutical compositions comprising a compound detailed herein and apharmaceutically acceptable carrier or excipient. In another variation,methods of administering a compound are provided. The purified forms,pharmaceutical compositions and methods of administering the compoundsare suitable for any compound or form thereof detailed herein.

The compound may be formulated for any available delivery route,including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal orrectal), parenteral (e.g., intramuscular, subcutaneous or intravenous),topical or transdermal delivery form. A compound may be formulated withsuitable carriers to provide delivery forms that include, but are notlimited to, tablets, caplets, capsules (such as hard gelatin capsules orsoft elastic gelatin capsules), cachets, troches, lozenges, gums,dispersions, suppositories, ointments, cataplasms (poultices), pastes,powders, dressings, creams, solutions, patches, aerosols (e.g., nasalspray or inhalers), gels, suspensions (e.g., aqueous or non-aqueousliquid suspensions, oil-in-water emulsions or water-in-oil liquidemulsions), solutions and elixirs.

One or several compounds described herein can be used in the preparationof a formulation, such as a pharmaceutical formulation, by combining thecompound or compounds as an active ingredient with a pharmaceuticallyacceptable carrier, such as those mentioned above. Depending on thetherapeutic form of the system (e.g., transdermal patch vs. oraltablet), the carrier may be in various forms. In addition,pharmaceutical formulations may contain preservatives, solubilizers,stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters,and salts for the adjustment of osmotic pressure, buffers, coatingagents or antioxidants. Formulations comprising the compound may alsocontain other substances which have valuable therapeutic properties.Pharmaceutical formulations may be prepared by known pharmaceuticalmethods. Suitable formulations can be found, e.g., in Remington: TheScience and Practice of Pharmacy, Lippincott Williams & Wilkins, 21^(st)ed. (2005), which is incorporated herein by reference.

Compounds as described herein may be administered to individuals (e.g.,a human) in a form of generally accepted oral compositions, such astablets, coated tablets, and gel capsules in a hard or in soft shell,emulsions or suspensions. Examples of carriers, which may be used forthe preparation of such compositions, are lactose, corn starch or itsderivatives, talc, stearate or its salts, etc. Acceptable carriers forgel capsules with soft shell are, for instance, plant oils, wax, fats,semisolid and liquid poly-ols, and so on. In addition, pharmaceuticalformulations may contain preservatives, solubilizers, stabilizers,re-wetting agents, emulgators, sweeteners, dyes, adjusters, and saltsfor the adjustment of osmotic pressure, buffers, coating agents orantioxidants.

Any of the compounds described herein can be formulated in a tablet inany dosage form described, for example, a compound as described hereinor a pharmaceutically acceptable salt thereof can be formulated as a 10mg tablet.

Compositions comprising a compound provided herein are also described.In one variation, the composition comprises a compound and apharmaceutically acceptable carrier or excipient. In another variation,a composition of substantially pure compound is provided.

Methods of Use

Compounds and compositions of the invention, such as a pharmaceuticalcomposition containing a compound of any formula provided herein or asalt thereof and a pharmaceutically acceptable carrier or excipient, maybe used in methods of administration and treatment as provided herein.The compounds and compositions may also be used in in vitro methods,such as in vitro methods of administering a compound or composition tocells for screening purposes and/or for conducting quality controlassays.

In one aspect, provided is a method of treating a fibrotic disease in anindividual in need thereof comprising administering to the individual atherapeutically effective amount of a compound of formula (I), or anyvariation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V),(Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, ora pharmaceutically acceptable salt thereof. In one aspect, theindividual is a human. The individual, such as human, may be in need oftreatment, such as a human who has or is suspected of having a fibroticdisease.

In another aspect, provided is a method of delaying the onset and/ordevelopment of a fibrotic disease in an individual (such as a human) whois at risk for developing a fibrotic disease. It is appreciated thatdelayed development may encompass prevention in the event the individualdoes not develop the fibrotic disease. An individual at risk ofdeveloping a fibrotic disease in one aspect has or is suspected ofhaving one or more risk factors for developing a fibrotic disease. Riskfactors for fibrotic disease may include an individual's age (e.g.,middle-age or older adults), the presence of inflammation, having one ormore genetic component associated with development of a fibroticdisease, medical history such as treatment with a drug or procedurebelieved to be associated with an enhanced susceptibility to fibrosis(e.g., radiology) or a medical condition believed to be associated withfibrosis, a history of smoking, the presence of occupational and/orenvironmental factors such as exposure to pollutants associated withdevelopment of a fibrotic disease.

In some embodiments, the fibrotic disease is fibrosis of a tissue suchas the lung (pulmonary fibrosis), the liver, the skin, the heart(cardiac fibrosis), the kidney (renal fibrosis), or the gastrointestinaltract (gastrointestinal fibrosis).

In some embodiments, the fibrotic disease is a pulmonary fibrosis, e.g.,idiopathic pulmonary fibrosis (IPF).

In some embodiments, the fibrotic disease is a primary sclerosingcholangitis, or biliary fibrosis.

In some embodiments, the fibrotic disease is fibrotic nonspecificinterstitial pneumonia (NSIP).

In some embodiments, the fibrotic disease is a liver fibrosis, e.g.,infectious liver fibrosis (from pathogens such as HCV, HBV or parasitessuch as schistosomiasis), NASH, alcoholic steatosis induced liverfibrosis, and cirrhosis.

In some embodiments, the fibrotic disease is biliary tract fibrosis.

In some embodiments, the fibrotic disease is kidney fibrosis, e.g.,diabetic nephrosclerosis, hypertensive nephrosclerosis, focal segmentalglomerulosclerosis (“FSGS”), and acute kidney injury from contrastinduced nephropathy.

In some embodiments, the fibrotic disease is systemic and localsclerosis or scleroderma, keloids and hypertrophic scars, or postsurgical adhesions.

In some embodiments, the fibrotic disease is atherosclerosis orrestenosis.

In some embodiments, the fibrotic disease is a gastrointestinalfibrosis, e.g., Crohn's disease.

In some embodiments, the fibrotic disease is cardiac fibrosis, e.g.,post myocardial infarction induced fibrosis and inheritedcardiomyopathy.

In one aspect, provided is a compound of formula (I), or any variationthereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or(Vb), a compound selected from Compound Nos. 1-31 in Table 1, or apharmaceutically acceptable salt thereof, for use in the treatment of afibrotic disease.

Also provided is use of a compound of formula (I), or any variationthereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V), (Va) or(Vb), a compound selected from Compound Nos. 1-31 in Table 1, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a fibrotic disease.

In another aspect, provided is a method of inhibiting αvβ6 integrin inan individual comprising administering a compound of formula (I), or anyvariation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V),(Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, ora pharmaceutically acceptable salt thereof.

Also provided is a method of inhibiting TGFβ activation in a cellcomprising administering to the cell a compound of formula (I), or anyvariation thereof, e.g., a compound of formula (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), (IVd), (V),(Va) or (Vb), a compound selected from Compound Nos. 1-31 in Table 1, ora pharmaceutically acceptable salt thereof.

Also provided is a method of inhibiting αvβ6 integrin in an individualin need thereof, comprising administering to the individual a compoundof formula (I), or any variation thereof, e.g., a compound of formula(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa),(IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected fromCompound Nos. 1-31 in Table 1, or a pharmaceutically acceptable saltthereof. In one such method, the compound is a selective αvβ6 integrininhibitor. In another such method, the compound does not inhibitsubstantially α4β1, αvβ8 and/or α2β3 integrin. In yet another suchmethod, the compound inhibits αvβ6 integrin but does not inhibitsubstantially α4β1 integrin. In still another such method, the compoundinhibits αvβ6 integrin but does not inhibit substantially αvβ8 integrin.In a further such method, the compound inhibits αvβ6 integrin but doesnot inhibit substantially α2β3 integrin. In one embodiment is provided amethod of inhibiting αvβ6 integrin and one or more of αvβ1, αvβ3, αvβ5,α2β1, α3β1, α6β1 integrin, α7β1 and α11β1 in an individual in needthereof. In another embodiment is provided a method of inhibiting αvβ6integrin and αvβ1 integrin. In another embodiment is provided a methodof inhibiting αvβ6 integrin, αvβ3 integrin and αvβ5 integrin. In anotherembodiment is provided a method of inhibiting αvβ6 integrin and α2β1integrin. In another embodiment is provided a method of inhibiting αvβ6integrin, α2β1 integrin and α3β1 integrin. In another embodiment isprovided a method of inhibiting αvβ6 integrin and α6β1 integrin. Inanother embodiment is provided a method of inhibiting αvβ6 integrin andα7β1 integrin. In another embodiment is provided a method of inhibitingαvβ6 integrin and α11β1 integrin. In all such embodiments, in one aspectthe method of inhibition is for an individual in need thereof, such asan individual who has or is suspected of having a fibrotic disease, andwherein the method comprises administering to the individual a compoundof formula (I), or any variation thereof, e.g., a compound of formula(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa),(IVb), (IVc), (IVd), (V), (Va) or (Vb), a compound selected fromCompound Nos. 1-31 in Table 1, or a pharmaceutically acceptable saltthereof.

In any of the described methods, in one aspect the individual is ahuman, such as a human in need of the method. The individual may be ahuman who has been diagnosed with or is suspected of having a fibroticdisease. The individual may be a human who does not have detectabledisease but who has one or more risk factors for developing a fibroticdisease.

Kits

The invention further provides kits for carrying out the methods of theinvention, which comprises one or more compounds described herein or apharmacological composition comprising a compound described herein. Thekits may employ any of the compounds disclosed herein. In one variation,the kit employs a compound described herein or a pharmaceuticallyacceptable salt thereof. The kits may be used for any one or more of theuses described herein, and, accordingly, may contain instructions foruse in the treatment of a fibrotic disease.

Kits generally comprise suitable packaging. The kits may comprise one ormore containers comprising any compound described herein. Each component(if there is more than one component) can be packaged in separatecontainers or some components can be combined in one container wherecross-reactivity and shelf life permit. One or more components of a kitmay be sterile and/or may be contained within sterile packaging.

The kits may be in unit dosage forms, bulk packages (e.g., multi-dosepackages) or sub-unit doses. For example, kits may be provided thatcontain sufficient dosages of a compound as disclosed herein (e.g., atherapeutically effective amount) and/or a second pharmaceuticallyactive compound useful for a disease detailed herein (e.g., fibrosis) toprovide effective treatment of an individual for an extended period,such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kitsmay also include multiple unit doses of the compounds and instructionsfor use and be packaged in quantities sufficient for storage and use inpharmacies (e.g., hospital pharmacies and compounding pharmacies).

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the methods of the present invention. Theinstructions included with the kit generally include information as tothe components and their administration to an individual.

SYNTHETIC EXAMPLES

The chemical reactions in the Synthetic Examples described can bereadily adapted to prepare a number of other compounds of the invention,and alternative methods for preparing the compounds of this inventionare deemed to be within the scope of this invention. For example, thesynthesis of non-exemplified compounds according to the invention can besuccessfully performed by modifications apparent to those skilled in theart, e.g., by appropriately protecting interfering groups, by utilizingother suitable reagents known in the art other than those described, orby making routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

Example 1 Synthesis of Tert-Butyl(R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidine-1-carboxylate

A flask equipped with a magnetic stir bar was charged with tert-butyl(R)-3-(2-(1,8-naphthyridin-2-yl)ethyl)pyrrolidine-1-carboxylate (3.10 g,9.47 mmol, 1.0 equiv) and 20 wt % Pd(OH)₂/C (310 mg) and then diluted inMeOH (31 mL). The flask was then evacuated and then backfilled with H₂for three cycles and then stirred under an H₂ atmosphere for 18 h, atwhich time, LC/MS had indicated complete conversion to the desiredproduct. The mixture was filtered through a pad of Celite andconcentrated in vacuo to give a crude residue that was purified bynormal phase silica gel chromatography (MeOH/EtOAc 0-20% gradient) togive tert-butyl(R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidine-1-carboxylate.MS (ESI+, m/e) 332 (M+1).

Example 2 Synthesis of(R)-7-(2-(pyrrolidin-3-yl)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridineDihydrochloride

A flask containing tert-butyl(R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidine-1-carboxylate(909 mg, 2.74 mmol, 1.0 equiv) was equipped with a stir bar then dilutedin 10:1 DCM/MeOH (9 mL). To this was then slowly added 4M HCl in dioxane(2.8 mL, 11.2 mmol, 4.1 equiv) and the mixture was allowed to stir atroom temperature for 4 hr and then concentrated in vacuo to give(R)-7-(2-(pyrrolidin-3-yl)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridinedihydrochloride that was used without further purification. MS (ESI+,m/e) 232 (M+1).

Example 3 Synthesis of Ethyl(S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate

To a solution of(R)-7-(2-(pyrrolidin-3-yl)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridinedihydrochloride (446 mg, 1.47 mmol, 1.0 equiv) in MeOH (5 mL) was addedAcOH (84 μL, 1.47 mmol, 1.0 equiv) then NaCNBH₃ (184 mg, 2.93 mmol, 2.0equiv) at room temperature. To this was then added ethyl(S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (607 mg, 2.48 mmol,1.7 equiv) and the resulting mixture was stirred for 1.5 hr at roomtemperature and then concentrated in vacuo. The crude residue waspurified by normal phase silica gel chromatography (2.0 M NH₃ inMeOH/EtOAc 0-30%) to give ethyl(S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate.MS (ESI+, m/e) 461 (M+1).

Example 4 Synthesis of Ethyl(S)-2-amino-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoateTrihydrochloride

A flask containing ethyl(S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate(605 mg, 1.31 mmol, 1.0 equiv) was equipped with a stir bar then dilutedin 10:1 DCM/MeOH (6 mL). To this was then slowly added 4M HCl in dioxane(1.3 mL, 5.2 mmol, 4.0 equiv) and the mixture was allowed to stir atroom temperature for 4 hr and then concentrated in vacuo to give ethyl(S)-2-amino-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoatetrihydrochloride that was used without further purification. MS (ESI+,m/e) 361 (M+1).

Example 5 General Procedure for Amide Coupling

A flask containing ethyl(S)-2-amino-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoatetrihydrochloride (50 mg, 0.1 mmol, 1.0 equiv) was diluted with 10:1THF/DMF (2 mL) and to this was added DIPEA (93 μL, 0.5 mmol, 5.0 equiv)followed by the appropriate carboxylic acid (1.5 equiv) and then HATU(57 mg, 0.15 mmol, 1.5 equiv) at room temperature. The resulting mixturewas stirred for 1 hr and then concentrated in vacuo to provide a cruderesidue that was purified by normal phase silica gel chromatography (2.0M NH₃ in MeOH/EtOAc 0-30%) to give the desired product.

Example 6 General Procedure for Hydrolysis

A flask containing the appropriate ester (50 mg, 1.0 equiv) was dilutedwith THF/MeOH/H₂O (1.0 mL) and to this was added LiOH (3.0 equiv) atroom temperature. The resulting mixture was stirred until LC/MSindicated complete hydrolysis of the ester to the desired carboxylicacid. The mixture was neutralized by the addition of AcOH (3.0 equiv)and then filtered through a 0.2 micron filter and purified bypreparative reverse phase HPLC (MeCN/H₂O containing 0.1% TFA, 5-95%gradient) to give the desired carboxylic acid as the trifluoroaceticacid salt.

Example 7 Synthesis of Exemplary Compounds

Certain exemplary compounds were synthesized using general proceduresdescribed herein, for example, procedures in Examples 5 and 6. Thestructures of the compounds and mass spectroscopy data (m/z) are listedbelow.

Compound No. Structure m/z  1a and 1c

417.2  2a

433.3  3a and 3c

437.2  4a and 4c

465.2  5a

489.2  6a

505.2  6c

505.1  7a and 7c

530.1  8a

505.2  9a

505.2 10a

505.2 11a

555.2 12a

545.3 13a and 13c

531.3 13a

531.3 13c

531.3 14a

522.3 15a

522.3 16a

522.3 17a

438.2 18a

438.2 19a

438.2 20a and 20c

506.1 21a

479.3 21c

479.3 22a

459.3 23a and 23c

484.3 24a

491.3 25a

491.3 26a

477.3 27a

491.3 28a

491.3 29a

527.2 30a

527.3 31a and 31c

478.2

BIOLOGICAL EXAMPLES Example B1—Solid Phase Integrin αvβ6 Binding Assay

Microplates were coated with recombinant human integrin αvβ6 (2 ug/ml)in PBS (100 ul/well 25° C., overnight). The coating solution wasremoved, washed with wash buffer (0.05% Tween 20; 0.5 mM MnCl2; in1×TBS). Plate was blocked with 200 ul/well of Block Buffer (1% BSA; 5%sucrose; 0.5 mM MnCl2; in 1×TBS) at 37° C. for 2 h. Dilutions of testingcompounds and recombinant TGFβ1 LAP (0.67 ug/ml) in binding buffer(0.05% BSA; 2.5% sucrose; 0.5 mM MnCl2; in 1×TBS) were added. The platewas incubated for 2 hours at 25° C., washed, and incubated for 1 hourwith Biotin-Anti-hLAP. Bound antibody was detected byperoxidase-conjugated streptavidin. The IC₅₀ values for testingcompounds were calculated by a four-parameter logistic regression.

The IC₅₀ values obtained for αvβ6 integrin inhibition for exemplarycompounds are shown in Table B-1. The compounds tested were compoundsamples prepared according to procedures described in the SyntheticExamples section, with the stereochemical purity as indicated in theExamples indicated.

TABLE B-1 Compound αvβ6 Inhibition IC₅₀ No. (nM) - range  1c <50  2a <50 3a and 3c <50  4a and 4c <50  5a <50  6a <50  6c 250-1000  7a and 7c<50  8a <50  9a <50  10a <50  11a <50  12a >1000  13a and 13c <50  13a<50  13c <50  14a 50-250  15a <50  16a >1000  17a 50-250  18a <50  19a50-250  20a and 20c <50  21a <50  21c <50  22a 50-250  23a and 23c50-250  24a <50  25a 50-250  26a <50  27a <50  28a <50  29a <50  30a <50 31a and 31c <50  33 >1000  34 >1000  35 <50  36 <50  37 <50  38 <50  3950-250  40 250-1000  41 50-250  42 250-1000  43 <50  44 <50  45 <50  46<50  47 <50  48 <50  49 <50  50 <50  51 <50  52 50-250  53 <50  54 <50 55 <50  56 <50  57 <50  58 <50  59 <50  60 <50  61 <50  62 50-250  6350-250  64 50-250  65 50-250  66 <50  67 <50  68 <50  69 50-250  70 <50 71 <50  72 <50  73 <50  74 <50  75 <50  76 <50  77 <50  78 <50  79 <50 80 <50  81 50-250  82 <50  83 <50  84 <50  85 <50  86 <50  87 <50  88<50  89 <50  90 <50  91 50-250  92 <50  93 50-250  94 50-250  95 <50  9650-250  97 50-250  98 250-1000  99 <50 100 50-250 101 250-1000 102250-1000 103 <50 104 <50 105 50-250 106 50-250 107 50-250 108 250-1000109 50-250 110 <50 111 >1000 112 >1000 113 >1000 114 250-1000 115 <50116 >1000 117 250-1000 118 250-1000 119 250-1000 120 50-250 121 250-1000122 250-1000 123 <50 124 50-250 125 250-1000 126 >1000 127 <50 128250-1000 129 250-1000 130 250-1000 131 50-250 132 50-250 133 250-1000134 250-1000 135 >1000 136 >1000 137 >1000 138 250-1000 139 250-1000140 >1000 141 <50 142 >1000 143 >1000 144 >1000 145 >1000 146 <50 147>1000

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

The invention claimed is:
 1. A compound of formula (I):

or a salt thereof, wherein: R¹ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, —OR²or —NR^(3a)R^(3b), wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclylof R¹ are independently optionally substituted by R¹⁰; R² is C₁-C₆alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, or3- to 12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to12-membered heterocyclyl of R² are independently optionally substitutedby R¹⁰; R^(3a) and R^(3b) are independently hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-memberedheterocyclyl of R^(3a) and R^(3b) are independently optionallysubstituted by R¹⁰; or R^(3a) and R^(3b) are taken together with thenitrogen to which they are attached to form a 4- to 8-memberedheterocyclyl optionally substituted by R¹⁰; n is 1 or 2; m is 0 to 6;each R⁵, where present, is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl,halogen, —CN, —OR^(5a), —C(O)OR^(5a), —NR^(5a)C(O)R^(5b);—NR^(5c)R^(5d), —C(O)NR^(5c)R^(5d), —SO₂R^(5e), or —SO₂NR^(5c)R^(5d),wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl are independentlyoptionally substituted by R¹⁰; each R^(5a) and R^(5b) is independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, or 3- to 12-membered heterocyclyl, wherein the C₁-C₆ alkyl,C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to12-membered heterocyclyl of R^(5a) and R^(5b) are independentlyoptionally substituted by R¹⁰; each R^(5c) and R^(5d) is independentlyhydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, or 3- to 12-membered heterocyclyl, wherein the C₁-C₆ alkyl,C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to12-membered heterocyclyl of R^(5c) and R^(5d) are independentlyoptionally substituted by R¹⁰; or R^(5c) and R^(5d) are taken togetherwith the nitrogen to which they are attached to form a 4- to 8-memberedheterocyclyl optionally substituted by R¹⁰; each R^(5e) is independentlyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-memberedheteroaryl, or 3- to 12-membered heterocyclyl, wherein the C₁-C₆ alkyl,C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to12-membered heterocyclyl of R^(5e) are independently optionallysubstituted by R¹⁰; X is C₁-C₃ alkylene optionally substituted by R¹⁰; pis 0 to 2; q is 0 to 6; each R⁷, where present, is independently C₁-C₆alkyl optionally substituted by halogen or —OH, C₃-C₆ cycloalkyl,halogen, —CN, —NO₂, —OR^(7a), or —NR^(7b)R^(7c); each R^(7a), R^(7b) andR^(7c) is independently hydrogen or C₁-C₃ alkyl; each R⁸, where present,is independently C₁-C₆ alkyl, C₃-C₆ cycloalkyl; halogen, oxo or—OR^(8a), wherein the C₁-C₆ alkyl and C₃-C₆ cycloalkyl are independentlyoptionally substituted by R¹⁰; R^(8a) is hydrogen or C₁-C₆ alkyl; eachR⁹ is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen,—CN, —OR¹¹, —SR¹¹, —NR¹²R¹³, —NO₂, —C═NH(OR¹¹), —C(O)R¹¹, —OC(O)R¹¹,—C(O)OR¹¹, —C(O)NR¹²R¹³, —NR¹¹C(O)R¹², NR¹¹C(O)OR¹², —NR¹¹C(O)NR¹²R¹³,—S(O)R¹¹, —S(O)₂R¹¹, —NR¹¹S(O)R¹², —NR¹¹S(O)₂R¹², —S(O)NR¹²R¹³,—S(O)₂NR¹²R¹³, —P(O)(OR¹²) (OR¹³), C₃-C₈ cycloalkyl, 3- to 12-memberedheterocyclyl, 5- to 10-membered heteroaryl, C₆-C₁₄ aryl, wherein each R⁹is independently optionally substituted by halogen, oxo, —OR¹⁴—NR¹⁴R¹⁵,—C(O)R¹⁴, —CN, —S(O)R¹⁴, —S(O)₂R¹⁴, —P(O)(OR¹⁴)(OR¹⁵), C₃-C₈ cycloalkyl,3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C₆-C₁₄aryl, or C₁-C₆ alkyl optionally substituted by oxo, —OH or halogen; eachR¹⁰ is independently oxo or R⁹; R¹¹ is independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein theC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl areindependently optionally substituted by halogen, oxo, —CN, —OR¹⁶,—NR¹⁶R¹⁷, P(O)(OR¹⁶)(OR¹⁷), or C₁-C₆ alkyl optionally substituted byhalogen, —OH or oxo; R¹² and R¹³ are each independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein theC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl areindependently optionally substituted by halogen, oxo, —CN, —OR¹⁶,—NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substituted by halogen, —OH or oxo;or R¹² and R¹³ are taken together with the atom to which they attachedto form a 3- to 6-membered heterocyclyl optionally substituted byhalogen, oxo, —OR¹⁶, —NR¹⁶R¹⁷ or C₁-C₆ alkyl optionally substituted byhalogen, oxo or —OH; R¹⁴ and R¹⁵ are each independently hydrogen, C₁-C₆alkyl optionally substituted by halogen or oxo, C₂-C₆ alkenyl optionallysubstituted by halogen or oxo, or C₂-C₆ alkynyl optionally substitutedby halogen or oxo; or R¹⁴ and R¹⁵ are taken together with the atom towhich they attached to form a 3- to 6-membered heterocyclyl optionallysubstituted by halogen, oxo or C₁-C₆ alkyl optionally substituted byhalogen or oxo; and R¹⁶ and R¹⁷ are each independently hydrogen, C₁-C₆alkyl optionally substituted by halogen or oxo, C₂-C₆ alkenyl optionallysubstituted by halogen or oxo, or C₂-C₆ alkynyl optionally substitutedby halogen or oxo; or R¹⁶ and R¹⁷ are taken together with the atom towhich they attached to form a 3-6 membered heterocyclyl optionallysubstituted by halogen, oxo or C₁-C₆ alkyl optionally substituted by oxoor halogen.
 2. The compound of claim 1, wherein the compound is of theformula (Ia):

or a salt thereof.
 3. The compound of claim 1, or a salt thereof,wherein n is
 1. 4. The compound of claim 1, or a salt thereof, wherein nis
 2. 5. The compound of claim 1, or a salt thereof, wherein X is C₁-C₃alkylene.
 6. The compound of claim 1, or a salt thereof, wherein X isC₁-C₂ alkylene optionally substituted by R¹⁰.
 7. The compound of claim1, or a salt thereof, wherein X is ethylene.
 8. The compound of claim 1,wherein the compound is of the formula (IVa):

or a salt thereof.
 9. The compound of claim 1, or a salt thereof,wherein R¹ is a C₁-C₆ alkyl optionally substituted by R¹⁰.
 10. Thecompound of claim 9, wherein R¹ is t-butyl.
 11. The compound of claim 1,or a salt thereof, wherein R¹ is —OR² or —NR^(3a)R^(3b).
 12. Thecompound of claim 11, or a salt thereof, wherein R¹ is —OR².
 13. Thecompound of claim 12, or a salt thereof, wherein R² is C₁-C₆ alkyl. 14.The compound of claim 13, wherein R² is t-butyl.
 15. The compound ofclaim 1, or a salt thereof, wherein R¹ is C₃-C₈ cycloalkyl optionallysubstituted by R¹⁰.
 16. The compound of claim 1, or a salt thereof,wherein R¹ is C₆-C₁₄ aryl optionally substituted by R¹⁰.
 17. Thecompound of claim 1, or a salt thereof, wherein R¹ is phenyl optionallysubstituted by R¹⁰.
 18. The compound of claim 1, or a salt thereof,wherein R¹ is 5- to 10-membered heteroaryl optionally substituted byR¹⁰.
 19. The compound of claim 18, or a salt thereof, wherein R¹ ispyridyl optionally substituted by R¹⁰.
 20. The compound of claim 18, ora salt thereof, wherein R¹ is indazolyl optionally substituted by R¹⁰.21. The compound of claim 1, or a salt thereof, wherein R¹ is 3- to12-membered heterocyclyl optionally substituted by R¹⁰.
 22. The compoundof claim 21, or a salt thereof, wherein R¹ is piperidinyl optionallysubstituted by R¹⁰.
 23. The compound of claim 21, or a salt thereof,wherein R¹ is tetrahydropyranyl optionally substituted by R¹⁰.
 24. Thecompound of claim 1, or a salt thereof, wherein R¹ is C₃-C₈ cycloalkyloptionally substituted by R¹⁰.
 25. The compound of claim 24, or a saltthereof, wherein R¹ is cyclohexyl optionally substituted by R¹⁰.
 26. Thecompound of claim 1, or a salt thereof, wherein R¹ is selected from thegroup consisting of:


27. The compound of claim 1, wherein the compound is selected from2-pivalamido-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-pivalamido-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-pivalamido-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-pivalamido-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-pivalamido-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-((tert-butoxycarbonyl)amino)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((tert-butoxycarbonyl)amino)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-((tert-butoxycarbonyl)amino)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-benzamido-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-benzamido-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-benzamido-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-benzamido-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-benzamido-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(2,6-dimethylbenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dimethylbenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dimethylbenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2,6-dimethylbenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2,6-dimethylbenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(2-chloro-3-fluorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-chloro-3-fluorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-chloro-3-fluorobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2-chloro-3-fluorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2-chloro-3-fluorobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2,6-dichlorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2,6-dichlorobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(2,6-dichloro-4-cyanobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichloro-4-cyanobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichloro-4-cyanobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2,6-dichloro-4-cyanobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2,6-dichloro-4-cyanobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(2-(trifluoromethyl)benzamido)butanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(2-(trifluoromethyl)benzamido)butanoicacid,(S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(2-(trifluoromethyl)benzamido)butanoicacid,(R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(2-(trifluoromethyl)benzamido)butanoicacid,(R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(2-(trifluoromethyl)benzamido)butanoicacid,4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(trifluoromethyl)benzamido)butanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(trifluoromethyl)benzamido)butanoicacid,(S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(trifluoromethyl)benzamido)butanoicacid,(R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(trifluoromethyl)benzamido)butanoicacid,(R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(trifluoromethyl)benzamido)butanoicacid,4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(4-(trifluoromethyl)benzamido)butanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(4-(trifluoromethyl)benzamido)butanoicacid,(S)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(4-(trifluoromethyl)benzamido)butanoicacid,(R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(4-(trifluoromethyl)benzamido)butanoicacid,(R)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(4-(trifluoromethyl)benzamido)butanoicacid,2-(2,6-dichlorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2,6-dichlorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-11dyl)butanoicacid,(R)-2-(2,6-dichlorobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(R)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-(4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(2-morpholinobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-morpholinobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-morpholinobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-morpholinobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(2-morpholinobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(3-morpholinobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-morpholinobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-morpholinobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(3-morpholinobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(3-morpholinobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(4-morpholinobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(4-morpholinobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(4-morpholinobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(4-morpholinobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(4-morpholinobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(picolinamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(picolinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(picolinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(picolinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(picolinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(isonicotinamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(isonicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(isonicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(isonicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(isonicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(nicotinamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(nicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(nicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(nicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(nicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(3,5-dichloroisonicotinamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3,5-dichloroisonicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3,5-dichloroisonicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(3,5-dichloroisonicotinamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(3,5-dichloroisonicotinamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(4,4-difluorocyclohexane-1-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(4-methyltetrahydro-2H-pyran-4-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(1-cyclopropylpiperidine-4-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-cyclopropylpiperidine-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-cyclopropylpiperidine-4-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-cyclopropylpiperidine-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-cyclopropylpiperidine-4-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(1-methyl-1H-indazole-6-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-indazole-6-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-indazole-6-carboxamido)-4-((s)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(r)-2-(1-methyl-1H-indazole-6-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(r)-2-(1-methyl-1H-indazole-6-carboxamido)-4-((s)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(1-methyl-1H-indazole-5-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-indazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-indazole-5-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-methyl-1H-indazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-methyl-1H-indazole-5-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(1H-indazole-7-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1H-indazole-7-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1H-indazole-7-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1H-indazole-7-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1H-indazole-7-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(1-methyl-1H-indazole-4-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-indazole-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-indazole-4-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-methyl-1H-indazole-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-methyl-1H-indazole-4-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(1-methyl-1H-indazole-7-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-indazole-7-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-indazole-7-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-methyl-1H-indazole-7-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-methyl-1H-indazole-7-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-(difluoromethyl)-1H-indazole-6-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(1-(difluoromethyl)-1H-indazole-5-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,2-(benzo[d]oxazole-5-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(benzo[d]oxazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(benzo[d]oxazole-5-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(benzo[d]oxazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(benzo[d]oxazole-5-carboxamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-formamido-4-hydroxybenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-carboxamido)piperidin-1-yl)butanoicacid,(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-(4-(((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)amino)piperidin-1-yl)butanoicacid,(S)-2-(1H-indazole-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)butanoicacid,(2S)-2-benzamido-4-(3,3-difluoro-4-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(2S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-difluoro-5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(2S)-2-benzamido-4-(3,3-difluoro-5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(2S)-4-(3,3-difluoro-5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)butanoicacid,(S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-methyl-2-phenylpropanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((R)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-cyanobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(pyrazine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(thiophene-2-carboxamido)butanoicacid,(S)-2-benzamido-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(2S)-2-benzamido-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(thiophen-2-yl)benzamido)butanoicacid,(S)-2-([1,1′-biphenyl]-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-(1-methyl-1H-pyrazol-5-yl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-(1-methyl-1H-pyrazol-4-yl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-(oxazol-2-yl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-isopropyl-1H-indazole-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-isobutyl-1H-indazole-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-chloro-3-fluorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(thiazol-4-yl)benzamido)butanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(thiazol-5-yl)benzamido)butanoicacid,(S)-2-(2,3-difluorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-(tert-butyl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-1H-pyrazole-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(pyrimidine-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-isopropyl-2H-indazole-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-isobutyl-2H-indazole-4-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-pentanoylpiperidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-(cyclobutanecarbonyl)piperidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-(2-chlorophenyl)acetamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-fluoro-5-(trifluoromethyl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-(2-hydroxy-2-methylpropyl)pyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((R)-1-pentanoylpiperidine-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((R)-1-pivaloylpiperidine-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((R)-1-(methoxycarbonyl)piperidine-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-benzylazetidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(1-methyl-3-phenyl-1H-indazole-7-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-([1,1′-biphenyl]-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(thiazol-5-yl)benzamido)butanoicacid,(R)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-2-(3-(thiazol-4-yl)benzamido)butanoicacid,(R)-2-(3-(1-methyl-1H-pyrazol-5-yl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(3-(1-methyl-1H-pyrazol-4-yl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(R)-2-(3-(oxazol-2-yl)benzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-4-benzylmorpholine-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-(pyrimidin-2-ylmethyl)pyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-(cyclopropylmethyl)pyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-(cyclobutylmethyl)pyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-benzylpiperidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-ethylbutanamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(2-ethylbutanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-morpholinobenzamido)butanoicacid,(S)-2-(3,5-difluorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(3-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-indazole-7-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-(pyridin-3-ylmethyl)pyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-(2-methoxyethoxy)benzamido)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-7-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-chloro-3-fluorobenzamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(3,5-difluorobenzamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(3-fluoro-5-(trifluoromethyl)benzamido)butanoicacid,(S)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(1-methyl-1H-indazole-6-carboxamido)butanoicacid,(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((R)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(2-ethylbutanamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-2-(4,4-difluorocyclohexane-1-carboxamido)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)butanoicacid,(S)-4-((S)-3-fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperidin-1-yl)-2-(1-methyl-1H-indazole-6-carboxamido)butanoicacid,(S)-2-((tert-butoxycarbonyl)amino)-4-((R)-3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-benzamido-4-((R)-3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamido)-4-((R)-3-((5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(S)-4-((S)-4-acetyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)piperazin-1-yl)-2-benzamidobutanoicacid,(S)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)butanoicacid,(S)-2-(2-methyl-2-phenylpropanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-methyl-2-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(S)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)-2-(tetrahydro-2H-pyran-4-carboxamido)butanoicacid,(S)-2-((R)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoicacid,(S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(S)-2-((R)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(S)-2-((S)-1-phenylpyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(2S)-2-(1-(2-hydroxy-2-methylpropyl)pyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)azetidin-1-yl)butanoicacid,(2S)-2-(1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoicacid,(S)-2-(2-methyl-2-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoicacid,(S)-2-(2,2-dimethyl-3-phenylpropanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoicacid,(S)-2-((S)-1-(pyridin-2-yl)pyrrolidine-3-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoicacid,(S)-2-(3-fluoro-5-(trifluoromethyl)benzamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoicacid,(S)-2-(3-fluoro-5-(trifluoromethyl)benzamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoicacid,(S)-2-((S)-1-(2-hydroxy-2-methylpropyl)pyrrolidine-2-carboxamido)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy)pyrrolidin-1-yl)butanoicacid,(S)-2-((S)-1-benzylpyrrolidine-2-carboxamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoicacid,(S)-2-(2-methyl-2-(pyridin-3-yl)propanamido)-4-(3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)azetidin-1-yl)butanoicacid,(S)-2-(2-ethylbutanamido)-4-((1R,2R,4S)-2-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)-7-azabicyclo[2.2.1]heptan-7-yl)butanoicacid,(S)-2-(2,6-dichlorobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid, or(R)-2-(2,6-dichlorobenzamido)-4-((S)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoicacid; or a salt thereof.
 28. A pharmaceutical composition comprising acompound of claim 1, or a salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 29. A method of treating a fibroticdisease in an individual in need thereof comprising administering acompound of claim 1 or a pharmaceutically acceptable salt thereof. 30.The method of claim 29, wherein the fibrotic disease is pulmonaryfibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, kidneyfibrosis, gastrointestinal fibrosis, primary sclerosing cholangitis, orbiliary fibrosis.
 31. A kit comprising a compound of claim 1, or apharmaceutically acceptable salt thereof.
 32. The kit of claim 31,further comprising instructions for the treatment of a fibrotic disease.33. A method of inhibiting αvβ6 integrin in an individual comprisingadministering a compound of claim 1 or a pharmaceutically acceptablesalt thereof.
 34. A method of inhibiting TGFβ activation in a cellcomprising administering to the cell a compound of claim 1 or apharmaceutically acceptable salt thereof.